Pyrazolo-triazine derivatives as ligands for gaba receptors

ABSTRACT

A class of substituted pyrazolo[1,5-d][1,2,4]triazine derivatives, possessing an optionally substituted cycloalkyl, phenyl or heteroaryl substituent at the 7-position, an alkyl group at the 4-position, and a substituted alkoxy moiety at the 2-position, are selective ligands for GABA A  receptors, in particular having high affinity for the α2 and/or α3 subunit thereof, and are accordingly of benefit in the treatment and/or prevention of disorders of the central nervous system, including anxiety and convulsions.

[0001] The present invention relates to a class of substitutedpyrazolo-triazine derivatives and to their use in therapy. Moreparticularly, this invention is concerned with substitutedpyrazolo[1,5-d][1,2,4]triazine derivatives which are ligands forGABA_(A) receptors and are therefore useful in the therapy ofdeleterious mental states.

[0002] Receptors for the major inhibitory neurotransmitter,gamma-aminobutyric acid (GABA), are divided into two main classes: (1)GABA_(A) receptors, which are members of the ligand-gated ion channelsuperfamily; and (2) GABA_(B) receptors, which may be members of theG-protein linked receptor superfamily. Since the first cDNAs encodingindividual GABA_(A) receptor subunits were cloned the number of knownmembers of the mammalian family has grown to include at least six αsubunits, four β subunits, three γ subunits, one δ subunit, one εsubunit and two ρ subunits.

[0003] Although knowledge of the diversity of the GABA_(A) receptor genefamily represents a huge step forward in our understanding of thisligand-gated ion channel, insight into the extent of subtype diversityis still at an early stage. It has been indicated that an α subunit, a βsubunit and a γ subunit constitute the minimum requirement for forming afully functional GABA_(A) receptor expressed by transiently transfectingcDNAs into cells. As indicated above, δ, ε and ρ subunits also exist,but are present only to a minor extent in GABA_(A) receptor populations.

[0004] Studies of receptor size and visualisation by electron microscopyconclude that, like other members of the ligand-gated ion channelfamily, the native GABA_(A) receptor exists in pentameric form. Theselection of at least one α, one β and one γ subunit from a repertoireof seventeen allows for the possible existence of more than 10,000pentameric subunit combinations. Moreover, this calculation overlooksthe additional permutations that would be possible if the arrangement ofsubunits around the ion channel had no constraints (i.e. there could be120 possible variants for a receptor composed of five differentsubunits).

[0005] Receptor subtype assemblies which do exist include, amongst manyothers, α1β2γ2, α2β2/3γ2, α3βγ2/3, α2βγ1, α5β3γ2/3, α6βγ2, α6βδ andα4βγ. Subtype assemblies containing an β1 subunit are present in mostareas of the brain and are thought to account for over 40% of GABA_(A)receptors in the rat. Subtype assemblies containing α2 and α3 subunitsrespectively are thought to account for about 25% and 17% of GABA_(A)receptors in the rat. Subtype assemblies containing an α5 subunit areexpressed predominantly in the hippocampus and cortex and are thought torepresent about 4% of GABA_(A) receptors in the rat.

[0006] A characteristic property of all known GABA_(A) receptors is thepresence of a number of modulatory sites, one of which is thebenzodiazepine (BZ) binding site. The BZ binding site is the mostexplored of the GABA_(A) receptor modulatory sites, and is the sitethrough which anxiolytic drugs such as diazepam and temazepam exerttheir effect. Before the cloning of the GABA_(A) receptor gene family,the benzodiazepine binding site was historically subdivided into twosubtypes, BZ1 and BZ2, on the basis of radioligand binding studies. TheBZ1 subtype has been shown to be pharmacologically equivalent to aGABA_(A) receptor comprising the α1 subunit in combination with a βsubunit and γ2. This is the most abundant GABA_(A) receptor subtype, andis believed to represent almost half of all GABA_(A) receptors in thebrain.

[0007] Two other major populations are the α2βγ2 and α3βγ2/3 subtypes.Together these constitute approximately a further 35% of the totalGABA_(A) receptor repertoire. Pharmacologically this combination appearsto be equivalent to the BZ2 subtype as defined previously by radioligandbinding, although the BZ2 subtype may also include certain α5-containingsubtype assemblies. The physiological role of these subtypes hashitherto been unclear because no sufficiently selective agonists orantagonists were known.

[0008] It is now believed that agents acting as BZ agonists at α1βγ2,α2βγ2 or α3βγ2 subunits will possess desirable anxiolytic properties.Compounds which are modulators of the benzodiazepine binding site of theGABA_(A) receptor by acting as BZ agonists are referred to hereinafteras “GABA_(A) receptor agonists”. The α1-selective GABA_(A) receptoragonists alpidem and zolpidem are clinically prescribed as hypnoticagents, suggesting that at least some of the sedation associated withknown anxiolytic drugs which act at the BZ1 binding site is mediatedthrough GABA_(A) receptors containing the α1 subunit. Accordingly, it isconsidered that GABA_(A) receptor agonists which interact morefavourably with the α2 and/or α3 subunit than with α1 will be effectivein the treatment of anxiety with a reduced propensity to cause sedation.Also, agents which are antagonists or inverse agonists at α1 might beemployed to reverse sedation or hypnosis caused by α1 agonists.

[0009] The compounds of the present invention, being selective ligandsfor GABA_(A) receptors, are therefore of use in the treatment and/orprevention of a variety of disorders of the central nervous system. Suchdisorders include anxiety disorders, such as panic disorder with orwithout agoraphobia, agoraphobia without history of panic disorder,animal and other phobias including social phobias, obsessive-compulsivedisorder, stress disorders including post-traumatic and acute stressdisorder, and generalized or substance-induced anxiety disorder;neuroses; convulsions; migraine; depressive or bipolar disorders, forexample single-episode or recurrent major depressive disorder, dysthymicdisorder, bipolar I and bipolar II manic disorders, and cyclothymicdisorder; psychotic disorders including schizophrenia; neurodegenerationarising from cerebral ischemia; attention deficit hyperactivitydisorder; and disorders of circadian rhythm, e.g. in subjectssuffering-from the effects of jet lag or shift work.

[0010] Further disorders for which selective ligands for GABA_(A)receptors may be of benefit include pain and nociception; emesis,including acute, delayed and anticipatory emesis, in particular emesisinduced by chemotherapy or radiation, as well as post-operative nauseaand vomiting; eating disorders including anorexia nervosa and bulimianervosa; premenstrual syndrome; muscle spasm or spasticity, e.g. inparaplegic patients; and hearing loss. Selective ligands for GABA_(A)receptors may also be effective as pre-medication prior to anaesthesiaor minor procedures such as endoscopy, including gastric endoscopy.

[0011] The present invention provides a class of pyrazolo-triazinederivatives which possess desirable binding properties at variousGABA_(A) receptor subtypes. The compounds in accordance with the presentinvention have good affinity as ligands for the α2 and/or α3 subunit ofthe human GABA_(A) receptor. The compounds of this invention mayinteract more favourably with the α2 and/or α3 subunit than with the α1subunit. Desirably, the compounds of the invention will exhibitfunctional selectivity in terms of a selective efficacy for the α2and/or α3 subunit relative to the α1 subunit.

[0012] The compounds of the present invention are GABA_(A) receptorsubtype ligands having a binding affinity (K_(i)) for the α2 and/or α3subunit, as measured in the assay described hereinbelow, of 100 nM orless, typically of 50 nM or less, and ideally of 10 nM or less. Thecompounds in accordance with this invention may possess at least a2-fold, suitably at least a 5-fold, and advantageously at least a10-fold, selective affinity for the α2 and/or α3 subunit relative to theα1 subunit. However, compounds which are not selective in terms of theirbinding affinity for the α2 and/or α3 subunit relative to the α1 subunitare also encompassed within the scope of the present invention; suchcompounds will desirably exhibit functional selectivity in terms of aselective efficacy for the α2 and/or α3 subunit relative to the α1subunit.

[0013] The present invention provides a compound of formula I, or a saltor prodrug thereof:

[0014] wherein

[0015] Y represents C₁₋₆ alkyl;

[0016] Z represents halogen; or C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C47cycloalkenyl, C₆₋₈ bicycloalkyl, aryl, C₃₋₇ heterocycloalkyl, heteroarylor di(C-₁₋₆)alkylamino, any of which groups may be optionallysubstituted;

[0017] R¹ represents C₃₋₇ cycloalkyl, phenyl, furyl, thienyl, pyridinylor pyrazinyl, any of which groups may be optionally substituted; and

[0018] R² represents C₃₋₇ cycloalkyl(C₁₋₆)alkyl, aryl(C₁₋₆)alkyl orheteroaryl(C₁₋₆)alkyl, any of which groups may be optionallysubstituted.

[0019] The groups Z, R¹ and R² may be unsubstituted, or substituted byone or more substituents, suitably by one, two or three substituents,and more particularly by one or two substituents. In general, the groupsZ, R¹ and R² will be unsubstituted or monosubstituted. Examples ofoptional substituents on the groups Z, R¹ and R² include C₁₋₆ alkyl,aryl(C₁₋₆)alkyl, pyridinyl(C₁₋₆)alkyl, halogen, halo(C₁₋₆)alkyl,dihalo(C₁₋₆)alkyl, trifluoromethyl, cyano, cyano(C₁₋₆)alkyl, hydroxy,hydroxymethyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl(C₁₋₆)alkoxy,cyano(C₁₋₆)alkoxy, C₃₋₇ cycloalkoxy, amino, amino(C₁₋₆)alkyl,di(C₁₋₆)alkylamino(C₁₋₆)alkyl, di(C₁₋₆)alkylaminocarbonyl(C₁₋₆)alkyl,N-(C₁₋₆)alkylpiperidinyl, pyrrolidinyl(C₁₋₆)alkyl,piperazinyl(C₁₋₆)alkyl, morpholinyl(C₁₋₆)alkyl,di-(C₁₋₆)alkylmorpholinyl(C₁₋₆)alkyl and imidazolyl(C₁₋₆)alkyl.Representative substituents include C₁₋₆ alkyl, halogen,halo(C₁₋₆)alkyl, dihalo(C₁₋₆)alkyl, trifluoromethyl, cyano, C₁₋₆ alkoxy,cyano(C₁₋₆)alkoxy, C₃₋₇ cycloalkoxy, amino anddi(C₁₋₆)alkylamino(C₁₋₆)alkyl, especially C₁₋₆ alkyl or halogen.Specific substituents include methyl, ethyl, n-propyl, isopropyl,fluoro, chloro, fluoroethyl, difluoroethyl, trifluoromethyl, cyano,methoxy, ethoxy, cyanomethoxy, cyclobutyloxy, amino anddimethylaminomethyl, especially methyl, ethyl or fluoro.

[0020] As used herein, the expression “C₁₋₆ alkyl” includes methyl andethyl groups, and straight-chained or branched propyl, butyl, pentyl andhexyl groups. Particular alkyl groups are methyl, ethyl, n-propyl,isopropyl, tert-butyl and 1,1-dimethylpropyl. Derived expressions suchas “C₁₋₆ alkoxy” are to be construed accordingly.

[0021] Typical C₃₋₇ cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

[0022] The expression “C₃₋₇ cycloalkyl(C₁₋₆)alkyl” as used hereinincludes cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl andcyclohexylmethyl.

[0023] Typical C₄₋₇ cycloalkenyl groups include cyclobutenyl,cyclopentenyl and cyclohexenyl.

[0024] Typical C₆₋₈ bicycloalkyl groups include bicyclo[2.1.1]hexyl andbicyclo[2.2.1]heptyl.

[0025] Typical aryl groups include phenyl and naphthyl, preferablyphenyl.

[0026] The expression “aryl(C₁₋₆)alkyl” as used herein includes benzyl,phenylethyl, phenylpropyl and naphthylmethyl, especially benzyl.

[0027] Suitable heterocycloalkyl groups include azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinylgroups.

[0028] Suitable heteroaryl groups include pyridinyl, quinolinyl,isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl,benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl,pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl andtetrazolyl groups. Further heteroaryl groups include[1,2,4]triazolo[1,5-a ]pyridinyl,5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a ]pyridinyl and5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a ]pyrazinyl groups.

[0029] The expression “heteroaryl(C₁₋₆)alkyl” as used herein includesfurylmethyl, furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl,oxazolylmethyl, oxazolylethyl, isoxazolylmethyl, thiazolylmethyl,thiazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl,oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl,thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl,tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyridazinylmethyl,pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl,isoquinolinylmethyl and quinoxalinylmethyl. The expression“heteroaryl(C₁₋₆)alkyl” as used herein further includes[1,2,4]triazolo[1,5-a ]pyridinylmethyl,5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a ]pyridinylmethyl and5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a ]pyrazinylmethyl.

[0030] The term “halogen” as used herein includes fluorine, chlorine,bromine and iodine, especially fluorine or chlorine.

[0031] For use in medicine, the salts of the compounds of formula I willbe pharmaceutically acceptable salts. Other salts may, however, beuseful in the preparation of the compounds according to the invention orof their pharmaceutically acceptable salts. Suitable pharmaceuticallyacceptable salts of the compounds of this invention include acidaddition salts which may, for example, be formed by mixing a solution ofthe compound according to the invention with a solution of apharmaceutically acceptable acid such as hydrochloric acid, sulphuricacid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid,acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid,carbonic acid or phosphoric acid. Furthermore, where the compounds ofthe invention carry an acidic moiety, suitable pharmaceuticallyacceptable salts thereof may include alkali metal salts, e.g. sodium orpotassium salts; alkaline earth metal salts, e.g. calcium or magnesiumsalts; and salts formed with suitable organic ligands, e.g. quaternaryammonium salts.

[0032] The present invention includes within its scope prodrugs of thecompounds of formula I above. In general, such prodrugs will befunctional derivatives of the compounds of formula I which are readilyconvertible in vivo into the required compound of formula I.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in Design of Prodrugs,ed. H. Bundgaard, Elsevier, 1985.

[0033] Where the compounds according to the invention have at least oneasymmetric centre, they may accordingly exist as enantiomers. Where thecompounds according to the invention possess two or more asymmetriccentres, they may additionally exist as diastereoisomers. It is to beunderstood that all such isomers and mixtures thereof in any proportionare encompassed within the scope of the present invention.

[0034] Typical values for the substituent Y include methyl and ethyl. Ina preferred embodiment, Y is methyl. In another embodiment, Y is ethyl.

[0035] Suitably, the substituent Z in the compounds of formula I aboverepresents halogen (e.g. bromo or iodo); or C₁₋₆ alkyl, C₃₋₇ cycloalkyl,aryl or heteroaryl, any of which groups may be optionally substituted.Suitably, Z may represent C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl orheteroaryl, any of which groups may be optionally substituted. Moreparticularly, Z may represent C₃₋₇ cycloalkyl or aryl, either of whichgroups may be optionally substituted.

[0036] Suitable values for the substituent Z include tert-butyl,1,1-dimethylpropyl, cyclobutyl, cyclopentyl, phenyl, pyridinyl, furyland thienyl, any of which groups may be optionally substituted by one ormore substituents.

[0037] Typical values of Z include tert-butyl, cyclopentyl, cyclohexyl,phenyl, furyl and thienyl, any of which groups may be optionallysubstituted by one or more substituents.

[0038] Particular values of Z include cyclopentyl and phenyl, either ofwhich groups may be optionally substituted by one or more substituents.

[0039] Specific examples of optional substituents on the group Z includemethyl, fluoro, chloro, trifluoromethyl, cyano and amino. Particularsubstituents include fluoro, chloro and trifluoromethyl, especiallyfluoro.

[0040] Typical examples of suitable values for the substituent Z includemethyl, ethyl, isopropyl, tert-butyl, 1,1-dimethylpropyl,methyl-cyclopropyl, cyclobutyl, methyl-cyclobutyl, cyclopentyl,methyl-cyclopentyl, cyclohexyl, cyclobutenyl, bicyclo [2.1. 1]hex-1-yl,bicyclo [2.2. 1]hept-1-yl, phenyl, fluorophenyl, difluorophenyl,chlorophenyl, trifluoromethylphenyl, cyanophenyl, aminophenyl,pyrrolidinyl, methyl-pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, pyridinyl, furyl, thienyl, chloro-thienyl anddiethylamino.

[0041] Individual examples of Z include tert-butyl, cyclopentyl,cyclohexyl, phenyl, fluorophenyl, furyl and thienyl. Typically, Zrepresents cyclopentyl or fluorophenyl.

[0042] In a particular embodiment, the substituent Z represents C₃₋₇cycloalkyl, either unsubstituted or substituted by C₁₋₆ alkyl,especially methyl. Favourably, Z represents cyclobutyl, cyclopentyl orcyclohexyl, particularly cyclobutyl or cyclopentyl, especiallycyclopentyl.

[0043] In another embodiment, Z represents tert-butyl.

[0044] In a further embodiment, Z represents phenyl.

[0045] In a still further embodiment, Z represents fluorophenyl.

[0046] In an additional embodiment, Z represents furyl or thienyl.

[0047] Suitable values of R¹ include phenyl, thienyl and pyrazinyl, anyof which groups may be optionally substituted by one or moresubstituents.

[0048] Examples of typical optional substituents on the group R¹ includemethyl, fluoro, chloro and methoxy. Particular substituents includemethyl, fluoro and methoxy, especially fluoro.

[0049] Specific values of R¹ include cyclopropyl, phenyl, methylphenyl,fluorophenyl, difluorophenyl, trifluorophenyl, chlorophenyl,methoxyphenyl, furyl, thienyl, methyl-thienyl, pyridinyl and pyrazinyl.

[0050] Individual values of R¹ include phenyl, fluorophenyl,difluorophenyl, trifluorophenyl, thienyl and pyrazinyl.

[0051] More particularly, R¹ may represent unsubstituted ormonosubstituted phenyl. Most particularly, R¹ represents phenyl orfluorophenyl. In one specific embodiment, R¹ represents fluorophenyl.

[0052] Suitably, R² represents aryl(C₁₋₆)alkyl or heteroaryl(C₁₋₆)alkyl,either of which groups may be optionally substituted.

[0053] Suitable values for the substituent R² in the compounds accordingto the invention include cyclohexylmethyl, benzyl, pyrazolylmethyl,isoxazolylmethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl,benzimnidazolylmethyl, oxadiazolylmethyl, triazolylmethyl,tetrazolylmethyl, pyridinylmethyl, pyridazinylmethyl, pyrimidinylmethyl,pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl,quinoxalinylmethyl, [1,2,4]triazolo[1,5-a ]pyridinylmethyl,5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a ]pyridinylmethyl and5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a ]pyrazinylmethyl, any of whichgroups may be optionally substituted by one or more substituents.

[0054] In one embodiment, R² represents triazolylmethyl orpyridinylmethyl, either of which groups may be optionally substituted byone or more substituents.

[0055] Suitably, R² represents an optionally substituted triazolylmethylgroup.

[0056] Examples of suitable optional substituents on the group R²include C₁₋₆ alkyl, aryl(C₁₋₆)alkyl, pyridinyl(C₁₋₆)alkyl, halogen,halo(C₁₋₆)alkyl, dihalo(C₁₋₆)alkyl, cyano, cyano(C₁₋₆)alkyl,hydroxymethyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl(C₁₋₆)alkoxy,cyano(C₁₋₆)alkoxy, C₃₋₇ cycloalkoxy, amino(C₁₋₆)alkyl,di(C₁₋₆)alkylamino(C₁₋₆)alkyl, di(C₁₋₆)alkylaminocarbonyl(C₁₋₆)alkyl,N-(C₁₋₆)alkylpiperidinyl, pyrrolidinyl(C₁₋₆)alkyl,piperazinyl(C₁₋₆)alkyl, morpholinyl(Ci 6)alkyl anddi(C₁₋₆)alkylmorpholinyl(C₁₋₆)alkyl, especially C₁₋₆ alkyl.

[0057] Specific illustrations of particular substituents on the group R²include methyl, ethyl, n-propyl, isopropyl, benzyl, pyridinylmethyl,chloro, chloromethyl, fluoroethyl, difluoroethyl, cyano, cyanomethyl,hydroxymethyl, methoxy, ethoxy, cyclopropylmethoxy, cyanomethoxy,cyclobutyloxy, dimethylaminomethyl, aminoethyl, dimethylaminoethyl,dlimethylaminocarbonylmethyl, N-methylpiperidinyl, pyrrolidinylethyl,piperazinylethyl, morpholinylmethyl and diimethylmorpholinylmethyl.

[0058] Selected substituents for the group R² include methyl, ethyl,n-propyl and isopropyl, especially methyl or ethyl.

[0059] Representative values of R² includehydroxymethyl-cyclohexylmethyl, cyanobenzyl, hydroxymethyl-benzyl,dimethylaminomethyl-benzyl, pyrazolylmethyl, dimethyl-pyrazolylmethyl,methyl-isoxazolylmethyl, thiazolylmethyl, methyl-thiazolylmethyl,ethyl-thiazolylmethyl, methyl-thiazolylethyl, imidazolylmethyl,methyl-imidazolylmethyl, ethyl-imidazolylmethyl,benzyl-imidazolylmethyl, benzimidazolylmethyl,methyl-benzimidazolylmethyl, methyl-oxadiazolylmethyl, triazolylmethyl,methyl-triazolylmethyl, ethyl-triazolylmethyl, propyl-triazolylmethyl,isopropyl-triazolylmethyl, benzyl-triazolylmethyl,pyridinylmethyl-triazolylmethyl, fluoroethyl-triazolylmethyl,difluoroethyl-triazolylmethyl, cyanomethyl-triazolylmethyl,dimethylaminomethyl-triazolylmethyl, aminoethyl-triazolylmethyl,dimethylaminoethyl-triazolylmethyl,dimethylaminocarbonylmethyl-triazolylmethyl,N-methylpiperidinyl-triazolylmethyl, pyrrolidinylethyl-triazolylmethyl,piperazinylethyl-triazolylmethyl, morpholinylethyl-triazolylmethyl,methyl-tetrazolylmethyl, pyridinylmethyl, methyl-pyridinylmethyl,dimethyl-pyridinylmethyl, cyano-pyridinylmethyl,methoxy-pyridinylmethyl, ethoxy-pyridinylmethyl,cyclopropylmethoxy-pyridinylmethyl, cyanomethoxy-pyridinylmethyl,cyclobutyloxy-pyridinylmethyl, pyridazinylmethyl,chloro-pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl,quinolinylmethyl, isoquinolinylmethyl, quinoxalinylmethyl,[1,2,4]triazolo[1,5-a ]pyridinylmethyl,5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a ]pyridinylmethyl and5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a ]pyrazinylmethyl.

[0060] Specific values of R² include methyl-triazolylmethyl andethyl-triazolylmethyl.

[0061] In one embodiment, R² is methyl-triazolylmethyl. In anotherembodiment, R² is ethyl-triazolylmethyl.

[0062] A particular sub-class of compounds according to the invention isrepresented by the compounds of formula IIA, and salts and prodrugsthereof:

[0063] wherein

[0064] Y, Z and R¹ are as defined with reference to formula I above;

[0065] m is 1 or 2, preferably 1; and

[0066] R¹² represents aryl or heteroaryl, either of which groups may beoptionally substituted.

[0067] Suitably, R¹² represents phenyl, pyrazolyl, isoxazolyl,thiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, triazolyl,tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl,isoquinolinyl, quinoxalinyl, [1,2,4]triazolo[1,5-a ]pyridinyl,5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyridinyl or5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a ]pyrazinyl, any of which groupsmay be optionally substituted by or more substituents.

[0068] Suitable values of R¹² include triazolyl and pyridinyl, either ofwhich groups may be optionally substituted by one or more substituents.

[0069] A particular value of R¹² is optionally substituted triazolyl.

[0070] Examples of typical substituents on the group R¹² include C₁₋₆alkyl, aryl(C₁₋₆)alkyl, pyridinyl(C₁₋₆)alkyl, halogen, halo(C₁₋₆)alkyl,dihalo(C₁₋₆)alkyl, cyano, cyano(C₁₋₆)alkyl, hydroxymethyl, C₁₋₆ alkoxy,C₃₋₇ cycloalkyl(C₁₋₆)alkoxy, cyano(C₁₋₆)alkoxy, C₃₋₇ cycloalkoxy,amino(C₁₋₆)alkyl, di(C₁₋₆)alkylamino(C₁₋₆)alkyl,di(C₁₋₆)alkylaminocarbonyl(C₁₋₆)alkyl, N-(C₁₋₆)alkylpiperidinyl,pyrrolidinyl(C₁₋₆)alkyl, piperazinyl(C₁₋₆)alkyl, morpholinyl(C₁₋₆)alkyland di(C₁₋₆)alkylmorpholinyl(C₁₋₆)alkyl, especially C₁₋₆ alkyl.

[0071] Illustrative values of specific substituents on the group R¹²include methyl, ethyl, n-propyl, isopropyl, benzyl, pyridinylmethyl,chloro, chloromethyl, fluoroethyl, difluoroethyl, cyano, cyanomethyl,hydroxymethyl, methoxy, ethoxy, cyclopropylmethoxy, cyanomethoxy,cyclobutyloxy, dimethylaminomethyl, aminoethyl, dimethylaminoethyl,dimethylaminocarbonylmethyl, N-methylpiperidinyl, pyrrolidinylethyl,piperazinylethyl, morpholinylmethyl and dimethylmorpholinylmethyl.

[0072] Selected substituents for the group R¹² include methyl, ethyl,n-propyl, and isopropyl, especially methyl or ethyl.

[0073] Particular values of R¹² include cyanophenyl,hydroxymethyl-phenyl, dimethylaminomethyl-phenyl, pyrazolyl,dimethyl-pyrazolyl, methyl-isoxazolyl, thiazolyl, methyl-thiazolyl,ethyl-thiazolyl, imidazolyl, methyl-imidazolyl, ethyl-imidazolyl,benzyl-imidazolyl, benzimidazolyl, methyl-benzimidazolyl,methyl-oxadiazolyl, triazolyl, methyl-triazolyl, ethyl-triazolyl,propyl-triazolyl, isopropyl-triazolyl, benzyl-triazolyl,pyridinylmethyl-triazolyl, fluoroethyl-triazolyl,difluoroethyl-triazolyl, cyanomethyl-triazolyl,dimethylaminomethyl-triazolyl, aminoethyl-triazolyl,dimethylaminoethyl-triazolyl, dimethylaminocarbonylmethyl-triazolyl,N-methylpiperidinyl-triazolyl, pyrrolidinylethyl-triazolyl,piperazinylethyl-triazolyl, morpholinylethyl-triazolyl,methyl-tetrazolyl, pyridinyl, methyl-pyridinyl, dimethyl-pyridinyl,cyano-pyridinyl, methoxy-pyridinyl, ethoxy-pyridinyl,cyclopropylmethoxy-pyridinyl, cyanomethoxy-pyridinyl,cyclobutyloxy-pyridinyl, pyridazinyl, chloro-pyridazinyl, pyrimidinyl,pyrazinyl, quinolinyl, isoquinolinyl, quinoxalinyl,[1,2,4]triazolo[1,5-a ]pyridinyl,5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a ]pyridinyl and5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a ]pyrazinyl.

[0074] Specific values of R¹² include methyl-triazolyl andethyl-triazolyl.

[0075] In one embodiment, R¹² is methyl-triazolyl. In anotherembodiment, R¹² is ethyl-triazolyl.

[0076] A particular subset of the compounds of formula IIA above isrepresented by the compounds of formula IIB, and pharmaceuticallyacceptable salts thereof:

[0077] wherein

[0078] Y and R¹ are as defined with reference to formula I above;

[0079] Q represents the residue of a cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, phenyl, pyridinyl, furyl or thienyl ring;

[0080] R^(3a) represents hydrogen, methyl, fluoro, chloro,trifluoromethyl, cyano or amino;

[0081] R^(3b) represents hydrogen or fluoro; and

[0082] R⁴ represents hydrogen, methyl, ethyl, n-propyl, isopropyl,fluoroethyl or difluoroethyl.

[0083] In relation to formula IIB above, R¹ suitably represents phenyl,fluorophenyl, difluorophenyl, trifluorophenyl, furyl, thienyl, pyridinylor pyrazinyl, especially phenyl or fluorophenyl.

[0084] Suitably, Q represents the residue of a cyclopentyl, cyclohexyl,phenyl, furyl or thienyl ring.

[0085] In one embodiment of the compounds of formula IIB above, Qrepresents the residue of a cyclobutyl, cyclopentyl, phenyl, pyridinyl,furyl or thienyl ring. In a subset of this embodiment, Q represents theresidue of a cyclopentyl or phenyl ring.

[0086] In a particular embodiment, Q suitably represents the residue ofa cyclopentyl ring. In another embodiment, Q represents the residue of aphenyl ring.

[0087] Suitably, R^(3a)represents hydrogen or fluoro, typicallyhydrogen.

[0088] Typically, R^(3b) represents hydrogen.

[0089] Suitably, R⁴ represents methyl or ethyl.

[0090] Specific compounds within the scope of the present inventioninclude:

[0091]3,7-bis(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine;

[0092]3-(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-phenylpyrazolo[1,5-d][1,2,4]triazine;

[0093]3-cyclopentyl-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazine;

[0094]3-cyclopentyl-7-(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine;

[0095]3-cyclopentyl-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-4-methyl-7-phenyl-pyrazolo[1,5-d][1,2,4]triazine;

[0096]3-cyclopentyl-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-phenylpyrazolo[1,5-d][1,2,4]triazine;

[0097]3-tert-butyl-7-(2,5-difluorophenyl)-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-4-methylpyrazolo[1,5-d][1,2,4]triazine;

[0098]3-tert-butyl-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-(2,3,6-trifluorophenyl)pyrazolo[1,5-d][1,2,4]triazine;

[0099]3-(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-(pyrazin-2-yl)pyrazolo[1,5-d][1,2,4]triazine;

[0100]3,7-bis(2-fluorophenyl)-4-methyl-2-(1-methyl-1H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine;

[0101]2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-3-(2-fluorophenyl)-4-methyl-7-(thien-3-yl)pyrazolo[1,5-d][1,2,4]triazine;

[0102]3-(2-fluorophenyl)-4-methyl-2-(1-methyl-1H-[1,2,4]triazol-3-ylmethoxy)-7-(thien-3-yl)pyrazolo[1,5-d][1,2,4]triazine;

[0103]3-cyclohexyl-7-(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine;

[0104]7-(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-3-(thien-3-yl)pyrazolo[1,5-d][1,2,4]triazine;

[0105]7-(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-3-phenylpyrazolo[1,5-d][1,2,4]triazine;

[0106]7-(2-fluorophenyl)-3-(fur-3-yl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine;

[0107]7-(2-fluorophenyl)-4-methyl-2-(1-methyl-1H-[1,2,4]triazol-3-ylmethoxy)-3-(thien-3-yl)pyrazolo[1,5-d][1,2,4]triazine;

[0108]7-(2-fluorophenyl)-4-methyl-2-(1-methyl-1H-[1,2,3]triazol-4-ylmethoxy)-3-(thien-3-yl)pyrazolo[1,5-d][1,2,4]triazine;

[0109]7-(4-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-3-(thien-3-yl)pyrazolo[1,5-d][1,2,4]triazine;

[0110]7-(2,4-difluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-3-(thien-3-yl)pyrazolo[1,5-d][1,2,4]triazine;

[0111] and salts and prodrugs thereof.

[0112] Also provided by the present invention is a method for thetreatment and/or prevention of anxiety which comprises administering toa patient in need of such treatment an effective amount of a compound offormula I as defined above or a pharmaceutically acceptable saltthereof.

[0113] Further provided by the present invention is a method for thetreatment and/or prevention of convulsions (e.g. in a patient sufferingfrom epilepsy or a related disorder) which comprises administering to apatient in need of such treatment an effective amount of a compound offormula I as defined above or a pharmaceutically acceptable saltthereof.

[0114] The binding affinity (K_(i)) of the compounds according to thepresent invention for the α3 subunit of the human GABA_(A) receptor isconveniently as measured in the assay described hereinbelow. The α3subunit binding affinity (K_(i)) of the compounds of the invention isideally 10 nM or less, preferably 2 nM or less, and more preferably 1 nMor less.

[0115] The compounds according to the present invention will ideallyelicit at least a 40%, preferably at least a 50%, and more preferably atleast a 60%, potentiation of the GABA EC₂₀ response in stablytransfected recombinant cell lines expressing the α3 subunit of thehuman GABA_(A) receptor. Moreover, the compounds of the invention willideally elicit at most a 30%, preferably at most a 20%, and morepreferably at most a 10%, potentiation of the GABA EC₂₀ response instably transfected recombinant cell lines expressing the α1 subunit ofthe human GABA_(A) receptor.

[0116] The potentiation of the GABA EC₂₀ response in stably transfectedcell lines expressing the α3 and α1 subunits of the human GABA_(A)receptor can conveniently be measured by procedures analogous to theprotocol described in Wafford et al., Mol. Pharmacol., 1996, 50,670-678. The procedure will suitably be carried out utilising culturesof stably transfected eukaryotic cells, typically of stably transfectedmouse Ltk⁻ fibroblast cells.

[0117] The compounds according to the present invention exhibitanxiolytic activity, as may be demonstrated by a positive response inthe elevated plus maze and conditioned suppression of drinking tests(cf. Dawson et al., Psychopharmacology, 1995, 121, 109-117). Moreover,the compounds of the invention are substantially non-sedating, as may beconfirmed by an appropriate result obtained from the responsesensitivity (chain-pulling) test (cf. Bayley et al., J.Psychopharmacol., 1996, 10, 206-213).

[0118] The compounds according to the present invention may also exhibitanticonvulsant activity. This can be demonstrated by the ability toblock pentylenetetrazole-induced seizures in rats and mice, following aprotocol analogous to that described by Bristow et al. in J. Pharmacol.Exp. Ther., 1996, 279, 492-501.

[0119] In order to elicit their behavioural effects, the compounds ofthe invention will ideally be brain-penetrant; in other words, thesecompounds will be capable of crossing the so-called “blood-brainbarrier”. Preferably, the compounds of the invention will be capable ofexerting their beneficial therapeutic action following administration bythe oral route.

[0120] The invention also provides pharmaceutical compositionscomprising one or more compounds of this invention in association with apharmaceutically acceptable carrier. Preferably these compositions arein unit dosage forms such as tablets, pills, capsules, powders,granules, sterile parenteral solutions or suspensions, metered aerosolor liquid sprays, drops, ampoules, auto-injector devices orsuppositories; for oral, parenteral, intranasal, sublingual or rectaladministration, or for administration by inhalation or insufflation. Forpreparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a pharmaceutically acceptable saltthereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition may be readilysubdivided into equally effective unit dosage forms such as tablets,pills and capsules. This solid preformulation composition is thensubdivided into unit dosage forms of the type described above containingfrom 0.1 to about 500 mg of the active ingredient of the presentinvention. Typical unit dosage forms contain from 1 to 100 mg, forexample 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. Thetablets or pills of the novel composition can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permits theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

[0121] The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

[0122] In the treatment of anxiety, a suitable dosage level is about0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day,and especially about 0.05 to 5 mg/kg per day. The compounds may beadministered on a regimen of 1 to 4 times per day.

[0123] The compounds of formula I as defined above may be prepared by aprocess which comprises cyclising a compound of formula III:

[0124] wherein Y, Z, R¹ and R² are as defined above.

[0125] The cyclisation of compound III may conveniently be effected byheating compound III to an elevated temperature, e.g. (i) a temperaturein the region of 180-200° C., in the presence of a high-boiling mediumsuch as Dowtherm A; or (ii) the reflux temperature of an inert solventsuch as xylene, optionally in the presence of a proton source such astriethylamine hydrochloride.

[0126] The intermediates of formula III above may be prepared byreacting a compound of formula IV with a hydrazide derivative of formulaV:

[0127] wherein Y, Z, R¹ and R² are as defined above.

[0128] The reaction between compounds IV and V is conveniently effectedby heating the reactants, optionally in the presence of a proton sourcesuch as triethylamine hydrochloride, typically at reflux in an inertsolvent such as xylene.

[0129] In another procedure, the compounds of formula I as defined abovemay be prepared by a process which comprises reacting a compound offormula VI with a compound of formula VII:

[0130] wherein Y, Z, R¹ and R² are as defined above, and L¹ represents asuitable leaving group.

[0131] The leaving group L¹ is suitably a halogen atom, typicallychloro.

[0132] The reaction between compounds VI and VII is convenientlyeffected by stirring the reactants in a suitable solvent, typicallyN,N-dimethylformamide, in the presence of a base such as cesiumcarbonate or potassium carbonate.

[0133] Similarly, the intermediates of formula IV may be prepared byreacting a compound of formula VII as defined above with a compound offormula VIII:

[0134] wherein Y and Z are as defined above; under conditions analogousto those described above for the reaction between compounds VI and VII;followed by oxidation.

[0135] Oxidation of the CHYOH side-chain in the intermediate resultingfrom the reaction between compounds VII and VIII to the ketone YC=Oside-chain in the corresponding intermediate of formula IV is suitablyeffected by treatment with pyridinium dichromate, in which case thereaction is conveniently carried out in dichloromethane at roomtemperature.

[0136] In a further procedure, the compounds of formula I as definedabove may be prepared by a process which comprises reacting a compoundof formula IX with a compound of formula X:

[0137] wherein Y, Z, R¹ and R² are as defined above, and L² represents asuitable leaving group.

[0138] The leaving group L² is typically an arylsulfonyloxy moiety, e.g.p-toluenesulfonyloxy (tosyloxy).

[0139] The reaction between compounds IX and X is conveniently effectedby stirring the reactants in a suitable solvent, typicallyN,N-dimethylformamide, in the presence of a base such as sodium hydride.

[0140] The intermediates of formula IX above may be prepared by reactinga compound of formula V as defined above with a compound of formula XI:

[0141] wherein Y, Z and L² are as defined above.

[0142] The reaction between compounds V and XI is conveniently effectedby heating the reactants, optionally in the presence of a proton sourcesuch as triethylamine hydrochloride, typically at reflux in an inertsolvent such as xylene; followed if necessary by heating to atemperature in the region of 180° C. in the presence of a high-boilingmedium such as Dowtherm A.

[0143] In a still further procedure, the compounds of formula I asdefined above may be prepared by a process which comprises reacting acompound of formula XII with a compound of formula XIII:

[0144] wherein Y, Z, R¹ and R² are as defined above, L³ represents asuitable leaving group, and M represents —B(OH)₂ or a cyclic esterthereof formed with an organic diol, e.g. 1,3-propanediol, or Mrepresents —Sn(Alk)₃ in which Alk represents a C₁₋₆ alkyl group,typically n-butyl; in the presence of a transition metal catalyst.

[0145] The leaving group L³ is typically a halogen atom, e.g. bromo.

[0146] Where M represents —B(OH)₂ or a cyclic ester thereof, thetransition metal catalyst is suitablytris(dibenzylideneacetone)palladium(0), in which case the reactionbetween compounds XII and XIII is conveniently effected at an elevatedtemperature in a solvent such as 1,4-dioxane, typically in the presenceof tri-tert-butylphosphine and cesium carbonate.

[0147] Where M represents —Sn(Alk)₃, the transition metal catalyst issuitably tetrakis(triphenylphosphine)palladium(0), in which case thereaction between compounds XII and XIII is conveniently effected at anelevated temperature in a solvent such as 1,4-dioxane, typically in thepresence of copper(I) iodide.

[0148] The compounds of formula XIII above may be prepared by reacting acompound of formula VII as defined above with a compound of formula XIV:

[0149] wherein Y, R¹ and L³ are as defined above; under conditionsanalogous to those described above for the reaction between compounds VIand VII.

[0150] The intermediates of formula XIV in which the leaving group L³represents bromo may be prepared by bromination of a compound of formulaXV:

[0151] wherein Y and R¹ are as defined above.

[0152] The bromination reaction is conveniently effected by treating theappropriate compound of formula XV with bromine, typically in glacialacetic acid.

[0153] The intermediates of formula VII and X above may be prepared bythe procedures described in WO 98/04559, or by methods analogousthereto.

[0154] Where they are not commercially available, the starting materialsof formula V, VI, VIII, XI, XII and XV may be prepared by methodsanalogous to those described in the accompanying Examples, or bystandard methods well known from the art.

[0155] It will be understood that any compound of formula I initiallyobtained from any of the above processes may, where appropriate,subsequently be elaborated into a further compound of formula I bytechniques known from the art. Indeed, as will be appreciated, thecompounds of formula XIII in which L³ is halogen are compounds accordingto the invention in their own right. By way of example, a compound offormula I initially obtained wherein R² is unsubstituted may beconverted into a corresponding compound wherein R² is substituted,typically by standard alkylation procedures, for example by treatmentwith a haloalkyl derivative in the presence of sodium hydride andN,N-dimethylformamide, or with a hydroxyalkyl derivative in the presenceof triphenylphosphine and diethyl azodicarboxylate. Furthermore, acompound of formula I initially obtained wherein the R² substituent issubstituted by a halogen atom, e.g. chloro, may be converted into thecorresponding compound wherein the R² substituent is substituted by adi(C₁₋₆)alkylamino moiety by treatment with the appropriatedi(C₁₋₆)alkylamine, typically with heating in a solvent such as1,4-dioxane in a sealed tube.

[0156] Where the above-described processes for the preparation of thecompounds according to the invention give rise to mixtures ofstereoisomers, these isomers may be separated by conventional techniquessuch as preparative chromatography. The novel compounds may be preparedin racemic form, or individual enantiomers may be prepared either byenantiospecific synthesis or by resolution. The novel compounds may, forexample, be resolved into their component enantiomers by standardtechniques such as preparative HPLC, or the formation of diastereomericpairs by salt formation with an optically active acid, such as(−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaricacid, followed by fractional crystallization and regeneration of thefree base. The novel compounds may also be resolved by formation ofdiastereomeric esters or amides, followed by chromatographic separationand removal of the chiral auxiliary.

[0157] During any of the above synthetic sequences it may be necessaryand/or desirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

[0158] The following Examples illustrate the preparation of compoundsaccording to the invention.

[0159] The compounds in accordance with this invention potently inhibitthe binding of [³H]-flumazenil to the benzodiazepine binding site ofhuman GABA_(A) receptors containing the α2 or α3 subunit stablyexpressed in Ltk⁻ cells.

[0160] Reagents

[0161] Phosphate buffered saline (PBS).

[0162] Assay buffer: 10 mM KH₂PO₄, 100 mM KCl, pH 7.4 at roomtemperature.

[0163] [³H]-Flumazenil (18 nM for α1β3γ2 cells; 18 nM for α2β3γ2 cells;10 nM for α3β3γ2 cells) in assay buffer.

[0164] Flunitrazepam 100 μM in assay buffer.

[0165] Cells resuspended in assay buffer (1 tray to 10 ml).

[0166] Harvesting Cells

[0167] Supernatant is removed from cells. PBS (approximately 20 ml) isadded. The cells are scraped and placed in a 50 ml centrifuge tube. Theprocedure is repeated with a further 10 ml of PBS to ensure that most ofthe cells are removed. The cells are pelleted by centrifuging for 20 minat 3000 rpm in a benchtop centrifuge, and then frozen if desired. Thepellets are resuspended in 10 ml of buffer per tray (25 cm×25 cm) ofcells.

[0168] Assay

[0169] Can be carried out in deep 96-well plates or in tubes. Each tubecontains:

[0170] 300 μl of assay buffer.

[0171] 50 μl of [³H]-flumazenil (final concentration for α1β3γ2: 1.8 nM;for α2β3γ2: 1.8 nM; for α3β3γ2: 1.0 nM).

[0172] 50 μl of buffer or solvent carrier (e.g. 10% DMSO) if compoundsare dissolved in 10% DMSO (total); test compound or flunitrazepam (todetermine non-specific binding), 10 μM final concentration.

[0173] 100 μl of cells.

[0174] Assays are incubated for 1 hour at 40° C., then filtered usingeither a Tomtec or Brandel cell harvester onto GF/B filters followed by3×3 ml washes with ice cold assay buffer. Filters are dried and countedby liquid scintillation counting. Expected values for total binding are3000-4000 dpm for total counts and less than 200 dpm for non-specificbinding if using liquid scintillation counting, or 1500-2000 dpm fortotal counts and less than 200 dpm for non-specific binding if countingwith meltilex solid scintillant. Binding parameters are determined bynon-linear least squares regression analysis, from which the inhibitionconstant K_(i) can be calculated for each test compound.

[0175] The compounds of the accompanying Examples were tested in theabove assay, and all were found to possess a K_(i) value fordisplacement of [³H]-flumazenil from the α2 and/or α3 subunit of thehuman GABA_(A) receptor, of 100 nM or less.

EXAMPLE 13,7-Bis(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine

[0176] a) 3-(2-Fluorophenyl)-4-hydroxy-5-methyl-5H-furan-2-one

[0177] To 2-fluorophenylacetic acid (25 g, 0.16 mol) and methyl lactate(17 g, 0.16 mol) in THF (600 ml) was added 1,3-dicyclohexylcarbodiimide(34 g, 0.16 mol) and 4-dimethylaminopyridine (0.99 g, 8.1 mmol) at 5° C.The mixture was allowed to warm to room temperature and stirred undernitrogen overnight. The solvent was removed in vacuo, then the residuewas taken up in diethyl ether (300 ml), and the resulting slurry wasfiltered to remove insoluble material. The filtrate was concentrated invacuo, and the residual oil was dissolved in potassium tert-butoxidesolution (162 ml of a 1.0 M solution in tert-butanol). The mixture wasstirred at reflux for 16 h and was allowed to cool to room temperature.Water (300 ml) was added, and the solution was washed with diethyl ether(2×100 ml). The aqueous solution was acidified to pH 1 with 5 Nhydrochloric acid. The product formed an immiscible oil, whichsolidified upon standing. This was collected by filtration, washed withwater and dried at 50° C., yielding3-(2-fluorophenyl)-4-hydroxy-5-methyl-5H-furan-2-one as a pale yellowsolid (23.2 g). ¹H NMR (400 MHz, CDCl₃) δ 1.46 (3H, d, J=6.7 Hz), 5.00(1H, q, J=6.7 Hz), 7.22 (2H, m), 7.39 (2H, m), 12.50 (1H, br s).

[0178] b) Toluene-4-sulfonic Acid4-(2-fluorophenyl)-5-(1-hydroxyethyl)-1H-pyrazol -3-yl Ester

[0179] To 3-(2-fluorophenyl)-4-hydroxy-5-methyl-5H-furan-2-one (18.7 g,90 mmol) in ethanol (90 ml) was added hydrazine hydrate (24 ml, 0.45mol), and the mixture was stirred at reflux for 3 days. The solution wasconcentrated to approximately 30 ml, and was then stirred at 90° C. for1 week. Hydrazine hydrate (24 ml, 0.45 mol) was added, and the mixturewas stirred at 90° C. for another week. More hydrazine hydrate (24 ml,0.45 mol) was added, and the solution was stirred as before for 1 week,and was then allowed to concentrate to approximately 30 ml. Ethanol (90ml) and hydrazine hydrate (24 ml, 0.45 mol) were added, and the mixturewas heated at reflux for 1 week. The solvent was removed in vacuo,yielding a glassy foam. This was suspended in dichloromethane (200 ml)and tosyl chloride (20.4 g, 0.107 mol) and triethylamine (16.3 ml, 0.165mol) were added at 5° C. The solution was allowed to warm to roomtemperature and was stirred overnight. The mixture was washed withsaturated sodium chloride solution (1×100 ml), dried over magnesiumsulfate, and was then concentrated in vacuo. The residue was purified byflash chromatography on silica gel (20 to 50% ethyl acetate indichloromethane, UV detection), yielding toluene-4-sulfonic acid4-(2-fluorophenyl)-5-(l-hydroxyethyl)-1H-pyrazol-3-yl ester as a yellowglass, which solidified upon standing (17.6 g). ¹H NMR (400 MHz, CDCl₃)δ 1.33 (3H, d, J=6.6 Hz), 2.38 (3H, s), 5.01 (1H, q, J=6.6 Hz), 6.98(1H, m), 7.11 (3H, m), 7.27 (2H, m), 7.80 (2H, d, J=8.3 Hz), 10.30 (1H,br s); MS (ES⁺) m/e 377 [MH]⁺.

[0180] c) Toluene-4-sulfonic Acid5-acetyl-4-(2-fluorophenyl)-1H-pyrazol-3-yl Ester

[0181] To toluene-4-sulfonic acid4-(2-fluorophenyl)-5-(1-hydroxyethyl)-1H-pyrazol-3-yl ester (16.4 g,43.6 mmol) in dichloromethane (500 ml) was added pyridinium dichromate(19.7 g, 52.3 mmol) and the resulting slurry was stirred at roomtemperature for 1 h. The mixture was poured directly onto a column ofsilica gel, and the product was eluted off with ethyl acetate, yieldingtoluene-4-sulfonic acid 5-acetyl-4-(2-fluorophenyl)-1H-pyrazol -3-ylester as a yellow solid (8.64 g). ¹H NMR (400 MHz, CDCl₃) δ 2.16 (3H,s), 2.43 (3H, s), 7.09 (1H, m), 7.22 (3H, m), 7.34 (1H, m), 7.41 (1H,m), 7.65 (2H, d, J=6.8 Hz); MS (ES⁺) m/e 375 [MH]⁺.

[0182] d) Toluene-4-sulfonic Acid3,7-bis(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl Ester

[0183] Toluene-4-sulfonic acid5-acetyl-4-(2-fluorophenyl)-1H-pyrazol-3-yl ester (8.26 g, 22.1 mmol)and 2-fluorobenzhydrazide (3.85 g, 25.0 mmol) were stirred together inxylene (250 ml) at reflux overnight. The solvent was removed in vacuo,and the residue was heated in Dowtherm A at 180° C. for 2 h. The mixturewas poured directly onto a column of silica gel, and the Dowtherm waseluted off with dichloromethane before eluting the product off with 10%ethyl acetate in dichloromethane (UV detection). Toluene-4-sulfonic acid3,7-bis(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl esterwas obtained as a yellow solid (6.52 g). ¹H NMR (400 MHz, CDCl₃) δ 2.43(3H, s), 2.53 (3H, s), 7.17-7.37 (6H, m), 7.41-7.51 (2H, m), 7.63 (1H,m), 7.69 (3H, m); MS (ES⁺) m/e 493 [MH]⁺.

[0184] e)3,7-Bis(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine

[0185] To toluene-4-sulfonic acid3,7-bis(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester(200 mg, 0.407 mmol) and (2-methyl-2H-[1,2,4]triazol-3-yl)methanol (57.5mg, 0.0509 mmol; prepared as described in EP-A-170073) in DMF (5 ml) wasadded sodium hydride (23.7 mg of a 60% dispersion in mineral oil; 0.593mmol) and the mixture was stirred at room temperature for 30 min. Water(50 ml) was added, then the solvent was removed in vacuo, and theresidue was purified by flash chromatography on silica gel eluting with0 to 100% ethyl acetate in dichloromethane.3,7-Bis(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazinewas isolated as a gum, which solidified upon trituration under isohexane(75 mg). ¹H NMR (400 MHz, CDCl₃) δ 2.52 (3H, s), 3.73 (3H, s), 5.44 (1H,d, J=13 Hz), 5.49 (1H, d, J=13 Hz), 7.18-7.31 (3H, m), 7.36-7.46 (3H,m), 7.63 (1H, m), 7.78 (1H, m), 7.82 (1H, s); MS (ES⁺) m/e 434 [MH]⁺.Anal. Found C, 61.03; H, 4.08; N, 21.95%. C₂₂H₁₇F₂N₇O.0.1 C₆H₁₄ requiresC, 61.41; H, 4.20; N, 22.18%.

EXAMPLE 23-(2-Fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-phenylpyrazolo[1,5-d][1,2,4]triazine

[0186] a) Toluene-4-sulfonic Acid3-(2-fluorophenyl)-4-methyl-7-phenylpyrazolo[1,5-d][1,2,4]Triazin-2-ylEster

[0187] Toluene-4-sulfonic acid5-acetyl-4-(2-fluorophenyl)-1H-pyrazol-3-yl ester (1.0 g, 2.7 mmol;prepared as described in Example 1, steps a to c) was stirred withbenzhydrazide (400 mg, 2.9 mmol) in xylene (30 ml) at reflux overnight.The mixture was allowed to cool to room temperature. A solidcrystallised out of solution. This was separated by filtration, and wasrecrystallised from ethyl acetate, yielding toluene-4-sulfonic acid3-(2-fluorophenyl)-4-methyl-7-phenylpyrazolo[1,5-d][1,2,4]triazin-2-ylester as a white solid (694 mg). ¹H NMR (400 MHz, CDCl₃) δ 2.47 (3H, s),2.52 (3H, s), 7.19 (1H, t, J=8.9 Hz), 7.28 (3H, m), 7.41-7.52 (4H, m),7.61 (1H, m), 7.79 (2H, d, J=8.3 Hz), 8.25 (2H, d, J=7.5 Hz); MS (ES⁺)m/e 475 [MH]³⁰ .

[0188] b)3-(2-Fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-phenylpyrazolo[1,5-d][1,2,4]triazine

[0189] This compound was prepared using the procedure described inExample 1, step e, using toluene-4-sulfonic acid3-(2-fluorophenyl)-4-methyl-7-phenylpyrazolo[1,5-d][1,2,4]triazin-2-ylester instead of toluene -4-sulfonic acid3,7-bis(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-ylester. Data for the title compound: ¹H NMR (400 MHz, CDCl₃) δ 2.51 (3H,s), 3.82 (3H, s), 5.56 (1H, d, J=13 Hz), 5.61 (1H, d, J=13 Hz),7.19-7.28 (2H, m), 7.38 (1H, m), 7.44 (1H, m), 7.60 (3H, m), 7.86 (1H,s), 8.37 (2H, m); MS (ES⁺) m/e 416 [MH]⁺.

EXAMPLE 33-Cyclopentyl-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazine

[0190] a) Toluene-4-sulfonic Acid4-cyclopentyl-5-(1-hydroxyethyl)-1H-pyrazol-3-yl Ester

[0191] To a solution of methyl lactate (6.9 g, 66.5 mmol) and pyridine(5.9 ml, 1.1 molar eq) in diethyl ether (200 ml) at 0° C. was addeddropwise over 1 h 2-bromo-2-cyclopentylacetyl chloride (15 g, 1 molareq). The reaction mixture was allowed to warm to room temperature andstirred for 14 h. The solution was washed with water (1×100 ml) andbrine (1×100 ml), then dried (Na₂SO₄), filtered and concentrated invacuo to leave an oil (18.7 g). This oil was dissolved in a solution ofdiethyl ether (56 ml) and trimethylsilyl chloride (224 ml) in thepresence of zinc (18.33 g, 5 molar eq) and heated under reflux for 1 hwith rapid stirring. After this time, the reaction mixture was cooled inan ice bath and water (200 ml) was added slowly and cautiously withrapid stirring. Then 4 N sodium hydroxide solution was added carefullyuntil a pH of 14 was achieved and the aqueous layer was separated andwashed with diethyl ether (1×200 ml). The aqueous layer was thenacidified to pH 1 using conc. HCl and was extracted with dichloromethane(4×200 ml). The combined layers were dried (Na₂SO₄), filtered andevaporated under vacuum to give a crude tetronic acid (3.48 g). This wasdissolved in ethanol (80 ml) and after the addition of hydrazine hydrate(1.9 ml, 2 molar eq) the reaction mixture was heated under reflux for 14h. The solvents were removed by rotary evaporation under high vacuum toleave a crude pyrazolone (3.4 g). This was dissolved in dichloromethane(50 ml) with p-toluenesulfonyl chloride (3.3 g, 1 molar eq) and cooledto 0° C. whereupon triethylamine (2.88 ml, 1.2 molar eq) was addeddropwise. The reaction mixture was allowed to warm to room temperatureand stirred for 14 h. More dichloromethane (200 ml) was added to thesolution which was then washed with brine (1×100 ml), dried (MgSO₄),filtered and evaporated under vacuum to give a crude product which waspurified by chromatography on silica gel using 0 to 30% ethyl acetate inisohexane as eluent to give as a colourless oil toluene-4-sulfonic acid4-cyclopentyl-5-(1-hydroxyethyl)-1H-pyrazol-3-yl ester (3.65 g). ¹H NMR(360 MHz, CDCl₃) δ 1.49 (3H, d, J=6.6 Hz), 1.56-1.93 (8H, m), 2.45 (3H,s), 2.77 (1H, m), 5.03 (1H, q, J=6.6 Hz), 7.35 (2H, d, J=8.5 Hz), 7.90(2H, d, J=8.5 Hz); MS (ES⁺) m/e 351[MH]⁺.

[0192] b) Toluene-4-sulfonic Acid 5-acetyl-4-cyclopentyl-1H—pyrazol-3-ylEster

[0193] To toluene-4-sulfonic acid4-cyclopentyl-5-(1-hydroxyethyl)-1H-pyrazol-3-yl ester (3.65 g, 10.43mmol) in dichloromethane (250 ml) was added pyridinium dichromate (3.92g, 1 molar eq) and the resulting slurry was stirred at room temperaturefor 1 h. The mixture was poured directly onto a column of silica gel,and the crude product was eluted off with ethyl acetate. Evaporation andfurther purification on silica gel using 0 to 20% ethyl acetate inisohexane as eluent yielded toluene-4-sulfonic acid5-acetyl-4-cyclopentyl-1H-pyrazol-3-yl ester as a colourless oil (1.36g). ¹H NMR (400 MHz, CDCl₃) δ 1.62-1.91 (81, m), 2.46 (3H, s), 2.53 (3H,s), 3.26 (1H, m), 7.37 (2H, d, J=6.8 Hz), 7.90 (2H, d, J=6.8 Hz); MS(ES⁺) m/e 349 [MH]⁺.

[0194] c) Toluene-4-sulfonic Acid3-cyclopentyl-7-(2-fluorophenyl-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-ylEster

[0195] Toluene-4-sulfonic acid 5-acetyl-4-cyclopentyl-1H-pyrazol-3-ylester (0.65 g, 1.87 mmol) and 2-fluorobenzhydrazide (0.317 g, 1.1 molareq) were stirred together in xylene (20 ml) at reflux for 2 h. Thesolvent was reduced to 5 ml and Dowtherm A (20 ml) was added and thereaction mixture was heated at 180° C. for 3 h. The mixture was cooledand poured directly onto a column of silica gel, and the Dowtherm waseluted off with dichloromethane before eluting the product off with 3-5%ethyl acetate in dichloromethane (UV detection). Toluene-4-sulfonic acid3-cyclopentyl-7-(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-ylester was obtained as a light brown solid (0.5 g). ¹H NMR (360 MHz,CDCl₃) δ 1.72-2.06 (8H, m), 2.42 (3H, s), 2.91 (3H, s), 3.46 (1H, m),7.16-7.33 (41, m), 7.58-7.65 (2H, m), 7.84 (2H, d, J=8.7 Hz); MS (ES⁺)m/e 467[MH]⁺.

[0196] d)3-Cyclopentyl-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazine

[0197] To toluene-4-sulfonic acid3-cyclopentyl-7-(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-ylester (230 mg, 0.494 mmol) and (2-ethyl-2H-[1,2,4]triazol-3-yl)methanol(75.6 mg, 1.2 molar eq; prepared as described in EP-A-170073) in DMF (10ml) was added sodium hydride (22 mg of a 60% dispersion in mineral oil;1.2 molar eq) and the mixture was stirred at room temperature for 1 h.Water (90 ml) was added then the solution was extracted with diethylether (4×50 ml). The combined ether layers were washed with brine (1×100ml), dried (Na₂SO₄), the solvent was removed in vacuo and the residuewas purified by flash chromatography on silica gel eluting with 0 to 50%ethyl acetate in dichloromethane.3-Cyclopentyl-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazinewas isolated as a gum, which solidified upon trituration under diethylether/isohexane (34.5 mg, mp=105° C.). ¹H NMR (360 MHz, CDCl₃) δ 1.36(3H, t, J=7.3 Hz), 1.53-1.91 (8H, m), 2.87 (3H, s), 3.41 (1H, m), 4.10(2H, q, J=7.3 Hz), 5.45 (2H, s), 7.23-7.36 (2H, m), 7.58-7.75 (2H, m),7.88 (1H, s); MS (ES⁺) m/e 422 [MH]⁺. Anal. Found C, 62.56; H, 5.67; N,23.18%. C₂₂H₂₄FN₇O requires C, 62.69; H, 5.74; N, 23.26%.

EXAMPLE 43-Cyclopentyl-7-(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine

[0198] To toluene-4-sulfonic acid3-cyclopentyl-7-(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-ylester (Example 3, step c; 230 mg, 0.494 mmol) and(2-methyl-2H-[1,2,4]triazol-3-yl)methanol (67 mg, 1.2 molar eq; preparedas described in EP-A-170073) in DMF (10 ml) was added sodium hydride (22mg of a 60% dispersion in mineral oil; 1.2 molar eq) and the mixture wasstirred at room temperature for 1 h. Water (90 ml) was added then thesolution was extracted with diethyl ether (4×50 ml). The combined etherlayers were washed with brine (1×100 ml), dried (Na₂SO₄), the solventwas removed in vacuo and the residue was purified by flashchromatography on silica gel eluting with 0 to 50% ethyl acetate indichloromethane.3-Cyclopentyl-7-(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazinewas isolated as a gum, which solidified upon trituration under diethylether/isohexane (77 mg, mp=123° C.). ¹H NMR (360 MHz, CDCl₃) δ 1.60-1.98(8H, m), 2.88 (3H, s), 3.42 (1H, m), 3.73 (3H, s), 5.44 (2H, s),7.22-7.37 (2H, m), 7.56-7.71 (2H, m), 7.85 (1H, s); MS (ES⁺) m/e 408[MH]⁺. Anal. Found C, 61.64; H, 5.31; N, 23.77%. C₂₁H₂₂FN₇O requires C,61.90; H, 5.44; N, 24.06%.

EXAMPLE 53-Cyclopentyl-2-(2-ethyl-2H-[1,2,4]Triazol-3-ylmethoxy)-4-methyl-7-phenyl-pyrazolo[1,5-d][1,2,4]triazine

[0199] a) Toluene-4-sulfonic Acid3-cyclopentyl-4-methyl-7-phenyl-pyrazolo[1,5-d][1,2,4]Triazin-2-yl Ester

[0200] Toluene-4-sulfonic acid 5-acetyl-4-cyclopentyl-1H-pyrazol-3-ylester (0.65 g, 1.87 mmol) and benzhydrazide (0.28 g, 1.1 molar eq) werestirred together in xylene (20 ml) at reflux for 2.5 h. The solvent wasreduced to ˜5 ml and Dowtherm A (20 ml) was added and the reactionmixture was heated at 180° C. for 2 h. The mixture was cooled and poureddirectly onto a column of silica gel, and the Dowtherm was eluted offwith dichloromethane before eluting the product off with 3-6% ethylacetate in dichloromethane (UV detection). Toluene-4-sulfonic acid3-cyclopentyl-4-methyl-7-phenylpyrazolo[1,5-d][1,2,4]triazin-2-yl esterwas obtained as a light brown solid (0.62 g). ¹H NMR (360 MHz, CDCl₃) δ1.73-2.07 (8H, m), 2.49 (3H, s), 2.91 (3H, s), 3.48 (1H, m), 7.26-7.61(5H, m), 7.93-7.97 (2H, m), 8.13-8.15 (2H, d, J=8.7 Hz); MS (ES⁺) m/e449 [MH]⁺.

[0201] b)3-Cyclopentyl-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-4-methyl-7-phenylpyrazolo[1,5-d][1,2,4]triazine

[0202] To toluene-4-sulfonic acid3-cyclopentyl-4-methyl-7-phenylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester(300 mg, 0.67 mmol) and (2-ethyl-2H-[1,2,4]triazol-3-yl)methanol (102mg, 1.2 molar eq; prepared as described in EP-A-170073) in DMF (10 ml)was added sodium hydride (29.5 mg of a 60% dispersion in mineral oil;1.2 molar eq) and the mixture was stirred at room temperature for 1 h.Water (90 ml) was added then the solution was extracted with diethylether (4×50 ml). The combined ether layers were washed with brine (1×100ml), dried (Na₂SO₄), the solvent was removed in vacuo and the residuewas purified by flash chromatography on silica gel eluting with 0 to 50%ethyl acetate in dichloromethane.3-Cyclopentyl-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-4-methyl-7-phenylpyrazolo[1,5-d][1,2,4]triazinewas isolated as a gum, which solidified upon trituration under diethylether/isohexane (144 mg, mp=112° C.). ¹H NMR (360 MHz, CDCl₃) δ 1.42(3H, t, J=7.3 Hz), 1.66-1.95 (8H, m), 2.87 (3H, s), 3.43 (1H, m), 4.20(2H, q, J=7.3 Hz), 5.55 (2H, s), 7.51-7.61 (3H, m), 7.93 (1H, s),8.28-8.31 (2H, m); MS (ES⁺) m/e 403 [MH]⁺. Anal. Found C, 65.10; H,6.06; N, 24.19%. C₂₂H₂₅N₇O requires C, 65.49; H, 6.25; N, 24.06%.

EXAMPLE 63-Cyclopentyl-4-methyl-2-(2-methyl-2H-[1,2,4]Triazol-3-ylmethoxy)-7-phenyl-pyrazolo[1,5-d][1,2,4]triazine

[0203] To toluene-4-sulfonic acid3-cyclopentyl-4-methyl-7-phenylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester(Example 5, step a; 300 mg, 0.67 mmol) and(2-methyl-2H-[1,2,4]triazol-3-yl)methanol (90.4 mg, 1.2 molar eq;prepared as described in EP-A-170073) in DMF (10 ml) was added sodiumhydride (29.5 mg of a 60% dispersion in mineral oil; 1.2 molar eq) andthe mixture was stirred at room temperature for 1 h. Water (90 ml) wasadded then the solution was extracted with diethyl ether (4×50 ml). Thecombined ether layers were washed with brine (1×100 ml), dried (Na₂SO₄),the solvent was removed in vacuo and the residue was purified by flashchromatography on silica gel eluting with 0 to 50% ethyl acetate indichloromethane. 3-Cyclopentyl-4-methyl-2-(2-methyl-2H[1,2,4]triazol-3-ylmethoxy)-7-phenylpyrazolo[1,5-d][1,2,4]triazine wasisolated as a gum, which solidified upon trituration under diethyl ether(152 mg, mp=159° C.). ¹H NMR (360 MHz, CDCl₃) δ 1.66-1.96 (8H, m), 2.86(3H, s), 3.44 (1H, m), 3.87 (3H, s), 5.54 (2H, s), 7.51-7.58 (3H, m),7.90 (1H, s), 8.24-8.26 (2H, m); MS (ES⁺) m/e 389 [MH]⁺. Anal. Found C,65.02; H, 5.97; N, 25.31%. C₂₁H₂₃N₇O requires C, 64.76; H, 5.95; N,25.18%.

EXAMPLE 73-tert-Butyl-7-(2,5-difluorophenyl-2-(2-ethyl-2H-[1,2,4]Triazol-3-ylmethoxy)-4-methylpyrazolo[1,5-d][1,2,4]triazine

[0204] a) 3-tert-Butyl-4-hydroxy-5-methyl-5H-furan-2-one

[0205] 4-Hydroxy-5-methyl-5H-furan-2-one (15.9 g, 0.14 mol) wasdissolved in tert-butanol (13.9 ml, 0.147 mol) with concentratedsulfuric acid (7.8 ml, 0.147 mol) and heated at 40° C. for 4 days. Thereaction mixture was allowed to cool and was partitioned between water(75 ml) and diethyl ether (75 ml). The organic layer was separated anddried (Na₂SO₄), filtered and concentrated under vacuum. Chromatographyon silica gel with diethyl ether as eluent gave a crude product whichwas further purified by chromatography on silica gel withdichloromethane as eluent then triturated with diethyl ether to give3-tert-butyl-4-hydroxy-5-methyl-5H-furan -2-one (3.1 g) as a whitesolid. ¹H NMR (360 MHz, CDCl₃) δ 1.34 (9H, s), 1.46 (3H, d, J=6.7 Hz),4.69 (1H, q, J=6.7 Hz).

[0206] b)4-tert-Butyl-5-(1-hydroxyethyl)-3-(4-methyl-phenyl)sulfonyloxypyrazole

[0207] 3-tert-Butyl-4-hydroxy-5-methyl-5H-furan-2-one (3 g, 17.7 mmol)was dissolved in ethanol (40 ml) with hydrazine hydrate (2.73 ml, 88.5mmol) and heated under reflux for 14 h. The volume was reduced byevaporation to ˜15 ml and heating continued for a further 48 h. Thesolvents were removed under high vacuum and the residue was trituratedwith diethyl ether to leave a white solid (crude4-tert-butyl-5-(1-hydroxyethyl)pyrazol-3-one, 2.6 g). This white solid(2.6 g, 14 mmol) was dissolved in dichloromethane (70 ml) with tosylchloride (3.24 g, 16.8 mmol) then cooled to 0° C. and triethylamine(2.56 ml, 18.2 mmol) was added dropwise. The reaction mixture wasallowed to warm to ambient temperature then diluted with moredichloromethane (50 ml) and washed with saturated brine (1×100 ml). Theorganic layer was dried (Na₂SO₄), filtered and concentrated under vacuumto leave a residue which was purified on silica gel using 20-50% ethylacetate in isohexane as eluent to give4-tert-butyl-5-(1-hydroxyethyl)-3-(4-methylphenyl)sulfonyloxypyrazole(3.8 g) as a white solid. ¹H NMR (360 MHz, CDCl₃) δ 1.34 (9H, s), 1.50(3H, d, J=6.7 Hz), 2.45 (3H, s), 5.26 (1H, q, J=6.7 Hz), 7.35 (2H, d,J=8.2 Hz), 7.95 (2H, d, J=8.2 Hz), 10.72 (1H, br s); MS (ES⁺) m/e 339[MH]⁺.

[0208] c) 5-Acetyl-4-tert-butyl-3-(4-methylphenyl)sulfonyloxypyrazole

[0209]4-tert-Butyl-5-(1-hydroxyethyl)-3-(4-methylphenyl)-sulfonyloxypyrazole(3.8 g, 11.3 mmol) was dissolved in dichloromethane (100 ml) and PDC(4.26 g, 11.3 mmol) was added. After stirring at ambient temperature for2 h, the reaction mixture was poured directly onto a silica gel columnand eluted with dichloromethane then 20% ethyl acetate/dichloromethaneto give the required product (2.71 g) as a white solid. ¹H NMR (360 MHz,CDCl₃) δ 1.26 (9H, s), 2.45 (3H, s), 2.56 (3H, s), 7.36 (2H, d, J=8.2Hz), 7.82 (2H, d, J=8.2 Hz), 10.70 (1H, br s); MS (ES⁺) m/e 337 [MH]⁺.

[0210] d) Toluene-4-sulfonic Acid3-tert-butyl-7-(2,5-difluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-ylEster

[0211] 5-Acetyl-4-tert-butyl-3-(4-methylphenyl)sulfonyloxypyrazole (0.4g, 1.19 mmol) was dissolved in xylene (20 ml) with 2,5-difluorobenzoichydrazide (0.225 g, 1.31 mmol) and heated under reflux for 14 h. Thexylene was removed by evaporation and replaced with Dowtherm A (15 ml)and heated at 180° C. for 4 h. The reaction mixture was allowed to coolto room temperature and poured directly onto a silica column and elutedwith dichloromethane then 1-5% ethyl acetate/dichloromethane to give therequired product (0.3 g) as a white solid. ¹H NMR (360 MHz, CDCl₃) δ1.64 (9H, s), 2.42 (3H, s), 3.11 (3H, s), 7.11-7.83 (8H, m); MS (ES⁺)m/e 473 [MH]⁺.

[0212] e)3-tert-Butyl-7-(2,5-difluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine

[0213] To toluene-4-sulfonic acid3-tert-butyl-7-(2,5-difluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-ylester (0.3 g, 0.636 mmol) and (2-ethyl-2H-[1,2,4]triazol-3-yl)methanol(97.3 mg, 1.2 molar eq; prepared as described in EP-A-170073) in DMF (10ml) was added sodium hydride (30 mg of a 60% dispersion in mineral oil;1.2 molar eq) and the mixture was stirred at room temperature for 1 h.Water (150 ml) was added then the solution was extracted with diethylether (4×50 ml). The combined ether layers were washed with brine (1×100ml), dried (Na₂SO₄), the solvent was removed in vacuo and the residuewas purified by flash chromatography on silica gel eluting with 0 to 50%ethyl acetate in dichloromethane.3-tert-Butyl-7-(2,5-difluorophenyl)-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-4-methylpyrazolo[1,5-d][1,2,4]triazinewas isolated as a gum, which solidified upon trituration under diethylether/isohexane (10 mg, mp=109° C.). ¹H NMR (360 MHz, CDCl₃) δ 1.40 (3H,t, J=7.3 Hz), 1.55 (9H, s), 3.08 (3H, s), 4.14 (2H, q, J=7.3 Hz), 5.48(2H, s), 7.18-7.41 (3H, m), 7.88 (1H, s); MS (ES⁺) m/e 428 [MH]⁺.

EXAMPLE 83-tert-Butyl-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-(2,3,6-trifluorophenyl)pyrazolo[1,5-d][1,2,4]triazine

[0214] a) 2,3,6-Trifluorobenzoic Hydrazide

[0215] To 2,3,6-trifluorobenzoyl chloride (29 g, 0.15 mol) indichloromethane (200 ml) was added methanol (30 ml) dropwise at 5° C.The solution was allowed to warm to room temperature and was stirredunder nitrogen for 2 h. The solvent was removed in vacuo and theresidual oil was stirred with hydrazine monohydrate (19 ml, 0.40 mol) inethanol (120 ml) at reflux for 3 h. The solvent was removed in vacuo,and the residue was partitioned between dichloromethane (400 ml) andwater (200 ml). The biphasic mixture was filtered to remove insolublematerial, then the aqueous layer was washed with dichloromethane (2×300ml). The combined organic layers were dried over magnesium sulfate, andwere concentrated in vacuo to yield 2,3,6-trifluorobenzoic hydrazide asa white solid (6.0 g). Data for the title compound: ¹H NMR (400 MHz,CDCl₃) δ 4.18 (2H, br s), 6.93 (1H, m), 7.25 (2H, m); MS (ES⁺) m/e 191[MH]⁺.

[0216] b) Toluene-4-sulfonic Acid3-tert-butyl-4-methyl-7-(2,3,6-trifluorophenyl)pyrazolo[1,5-d][1,2,4]triazin-2-ylEster

[0217] This compound was prepared using the procedure described inExample 7, step d, using 2,3,6-trifluorobenzoic hydrazide instead of2,5-difluorobenzoic hydrazide. Data for the title compound: ¹H NMR (360MHz, CDCl₃) δ 1.65 (9H, s), 2.42 (3H, s), 3.13 (3H, s), 6.98 (1H, m),7.21 (2H, d, J=8.2 Hz), 7.38 (1H, m), 7.74 (2H, d, J=8.4 Hz); MS (ES⁺)m/e 491 [MH]⁺.

[0218] c)3-tert-Butyl-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-(2,3,6-trifluorophenyl)pyrazolo[1,5-d][1,2,4]triazine

[0219] This compound was prepared using the procedure described inExample 7, step e, using (2-methyl-2H-[1,2,4]triazol-3-yl)methanol(prepared as described in EP-A-170073) instead of(2-ethyl-2H-[1,2,4]triazol-3-yl)methanol, and using toluene-4-sulfonicacid3-tert-butyl-4-methyl-7-(2,3,6-trifluorophenyl)pyrazolo[1,5-d][1,2,4]triazin-2-ylester instead of toluene-4-sulfonic acid3-tert-butyl-7-(2,5-difluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-ylester. Data for the title compound: ¹H NMR (400 MHz, CDCl₃) δ 1.55 (9H,s), 3.07 (3H, s), 3.84 (3H, s), 5.38 (2H, s), 7.04 (1H, m), 7.41 (1H,m), 7.86 (1H, s); MS (ES⁺) m/e 432 [MH]⁺.

EXAMPLE 93-(2-Fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-(-pyrazin-2—l)-pyrazolo[1,5-d][1,2,4]triazine

[0220] a) Toluene-4-sulfonic Acid3-(2-fluorophenyl)-4-methyl-7-(pyrazin-2-yl)pyrazolo[1,5-d][1,2,4]triazin-2-ylEster

[0221] This compound was prepared using the procedure described inExample 1, step d, using pyrazine carbohydrazide instead of2-fluorobenzhydrazide. Data for the title compound: ¹H NMR (400 MHz,CDCl₃) δ 2.46 (3H, s), 2.56 (3H, s), 7.20 (1H, t, J=9.2 Hz), 7.40 (3H,m), 7.42 (1H, td, J=7.4, 1.7 Hz), 7.49 (1H, m), 7.78 (2H, d, J=8.3 Hz);MS (ES⁺) m/e 477[MH]⁺.

[0222] b)3-(2-Fluoro-phenyl-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-(pyrazin-2-yl)pyrazolo[1,5-d][1,2,4]triazine

[0223] This compound was prepared using the procedure described inExample 7, step e, using (2-methyl-2H-[1,2,4]triazol-3-yl)methanol(prepared as described in EP-A-170073) instead of(2-ethyl-2H-[1,2,4]triazol-3-yl)methanol, and using toluene-4-sulfonicacid3-(2-fluorophenyl)-4-methyl-7-(pyrazin-2-yl)pyrazolo[1,5-d][1,2,4]triazin-2-ylester instead of toluene-4-sulfonic acid3-tert-butyl-7-(2,5-difluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester. Data for the titlecompound: ¹H NMR (400 MHz, CDCl₃) δ 2.54 (3H, s), 3.84 (3H, s), 5.54(1H, d, J=13 Hz), 5.58 (1H, d, J=13 Hz), 7.21 (1H, m), 7.26 (1H, m),7.36 (1H, td, J=7.4, 1.8 Hz), 7.46 (1H, m), 7.84 (1H, s), 8.85 (2H, m),9.48 (1H, d, J=1.4 Hz); MS (ES⁺) m/e 418 [MH]⁺. Anal. Found C, 57.37; H,3.73; N, 28.99%. C₂₀H₁₆FN₉O.0.3H₂O.0.07 C₆H₁₄ requires C, 57.19; H,4.13; N, 29.40%.

EXAMPLE 103,7-Bis(2-fluorophenyl)-4-methyl-2-(1-methyl-1H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine

[0224] This compound was prepared using the procedure described inExample 1, step e, using (1-methyl-1H-[1,2,4]-triazol-3-yl)methanol(prepared as described in WO 98/04559) instead of(2-methyl-2H-[1,2,4]triazol-3-yl)methanol. Data for the title compound:¹H NMR (400 MHz, CDCl₃) δ 2.51 (3H, s), 3.88 (3H, s), 5.37 (1H, d, J=12Hz), 5.45 (1H, d, J=12 Hz), 7.15-7.28 (3H, m), 7.33-7.40 (3H, m), 7.44(1H, td, J=7.4, 1.7 Hz), 7.59 (1H, m), 7.82 (1H, m), 7.97 (1H, s); MS(ES⁺) m/e 434 [MH]⁺.

EXAMPLE 112-(2-Ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-3-(2-fluoro-phenyl)-4-methyl-7-(thien-3-yl)pyrazolo[1,5-d][1,2,4]triazine

[0225] a) Toluene-4-sulfonic Acid3-(2-fluorophenyl)-4-methyl-7-(thien-3-yl)pyrazolo[1,5-d][1,2,4]triazin-2-ylEster

[0226] This compound was prepared using the procedure described inExample 1, step d, using thiophene-3-carbohydrazide instead of2-fluorobenzhydrazide. Data for the title compound: ¹H NMR (400 MHz,CDCl₃) δ 2.50 (3H, s), 2.51 (3H, s), 7.19 (1H, m), 7.29 (1H, td, J=7.5,0.8 Hz), 7.33 (2H, d, J=8.2 Hz), 7.41-7.52 (3H, m), 7.81 (2H, d, J=8.3Hz), 8.16 (1H, dd, J=5.1, 1.1 Hz), 8.57 (1H, dd, J=3.0, 1.1 Hz); MS(ES⁺) m/e 481 [MH]⁺.

[0227] b)2-(2-Ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-3-(2-fluorophenyl)-4-methyl-7-(thien-3-yl)pyrazolo[1,5-d][1,2,4]triazine

[0228] This compound was prepared as described in Example 7, step e,using toluene-4-sulfonic acid3-(2-fluorophenyl)-4-methyl-7-(thien-3-yl)pyrazolo[1,5-d][1,2,4]triazin-2-ylester instead of toluene-4-sulfonic acid3-tert-butyl-7-(2,5-difluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-ylester. Data for the title compound: ¹H NMR (400 MHz, CDCl₃) δ 1.32 (3H,t, J=7.2 Hz), 2.48 (3H, s), 4.21 (2H, q, J=7.2 Hz), 5.67 (1H, d, J=13Hz), 5.72 (1H, d, J=13 Hz), 7.18-7.27 (2H, m), 7.36 (1H, td, J=7.4, 1.7Hz), 7.42-7.49 (2H, m), 7.90 (1H, s), 8.28 (1H, dd, J=5.2, 1.2 Hz), 9.16(1H, m); MS (ES⁺) m/e 436 [MH]⁺. Anal. Found C, 58.01; H, 4.05; N,22.32%. C₂₁H₁₈FN₇OS requires C, 57.92; H, 4.17; N, 22.51%.

EXAMPLE 123-(2-Fluorophenyl)-4-methyl-2-(1-methyl-1H-[1,2,4]triazol-3-ylmethoxy)-7-(thien-3-yl)pyrazolo[1,5-d][1,2,4]triazine

[0229] This compound was prepared using the procedure described inExample 11, step b, using (1-methyl-1H-[1,2,4]triazol-3-yl)methanol(prepared as described in WO 98/04559) instead of(2-ethyl-2H-[1,2,4]triazol-3-yl)methanol. Data for the title compound:¹H NMR (400 MHz, CDCl₃) δ 2.48 (3H, s), 3.92 (3H, s), 5.56 (1H, d, J=12Hz), 5.63 (1H, d, J=12 Hz), 7.16-7.26 (2H, m), 7.38-7.47 (3H, m), 8.01(1H, s), 8.30 (1H, dd, J=5.2, 1.1 Hz), 9.27 (1H, dd, J=3.0, 1.1 Hz); MS(ES⁺) m/e 422 [MH]⁺. Anal. Found C, 56.87; H, 3.67; N, 22.99%.C₂₀H₁₆FN₇OS requires C, 57.00; H, 3.83; N, 23.26%.

EXAMPLE 133-Cyclohexyl-7-(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine

[0230] This compound was prepared using the procedure described inExample 3, steps a, b, c and d, using 2-bromo-2-cyclohexylacetylchloride in step a instead of 2-bromo-2-cyclopentylacetyl chloride, andusing (2-methyl-2H-[1,2,4]triazol-3-yl)methanol (prepared as describedin EP-A-170073) instead of (2-ethyl-2H-[1,2,4]triazol-3-yl)methanol instep d. Data for the title compound: ¹H NMR (400 MHz, CDCl₃) δ 1.26-1.38(3H, m), 1.74-1.86 (7H, m), 2.87 (3H, s), 3.02 (1H, m), 3.75 (3H, s),5.43 (2H, s), 7.24 (1H, m), 7.34 (1H, td, J=7.6, 0.9 Hz), 7.58 (1H, m),7.69 (1H, m), 7.85 (1H, s); MS (ES⁺) m/e 422 [MH]⁺. Anal. Found C,62.89; H, 5.68; N, 23.13%. C₂₂H₂₄FN₇O requires C, 62.29; H, 5.74; N,23.26%.

EXAMPLE 147-(2-Fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-3-(thien-3-yl)pyrazolo[1,5-d][1,2,4]triazine

[0231] a) (S)-3-Hydroxy-5-(1-hydroxyethyl)-1H-pyrazole

[0232] To a stirred solution of (S)-5-methyltetronic acid (prepared asdescribed by Brandange et al., J. Org. Chem., 1984, 49, 927) (12.32 g,0.108 mmol) in ethanol (85 ml) was added hydrazine hydrate (6.29 ml,0.130 mmol) and the mixture was heated at reflux for 5 h. The solventswere removed in vacuo and the residue was recrystallised fromethanol-ethyl acetate (1:1) to afford 10.49 g (76%) of the titlecompound: ¹H NMR (360 MHz, DMSO-d₆) δ 1.31 (3H, d, J=6.5 Hz), 4.60 (1H,m), 5.11 (1H, d, J 4.8 Hz), 5.30 (1H, s).

[0233] b) Toluene-4-sulfonic Acid 5-[(S)-1-hydroxyethyl]-1H-pyrazol-3-ylEster

[0234] To a stirred solution of(S)-3-hydroxy-5-(1-hydroxyethyl)-1H-pyrazole (0.5056 g, 3.95 mmol) inanhydrous dichloromethane (20 ml) under nitrogen was addedp-toluenesulfonyl chloride (0.8276 g, 4.34 mmol) then, dropwise,triethylamine (0.66 ml, 4.74 mmol). The mixture was stirred at roomtemperature for 3 h, then washed with saturated NaCl (15 ml). Theaqueous layer was further extracted with dichloromethane (2×25 ml) andthe combined organic extracts were dried (NaSO₄) and evaporated invacuo. The residue was purified by flash chromatography (silica gel, 5%MeOH/CH₂Cl₂) to give 0.8770 g (79%) of the title compound as an orangeoil: ¹H NMR (400 MHz, DMSO-d₆) δ 1.31 (3H, d, J=6.5 Hz), 2.42 (3H, s),4.67 (1H, m), 5.40 (1H, d, J=5.1 Hz), 5.79 (1H, d, J=2.1 Hz), 7.47 (2H,d, J=8.1 Hz), 7.77 (2H, d, J=8.4 Hz), 12.48 (1H, s); MS (ES⁺) m/e 283[M+H]⁺, 265 [M-OH]⁺.

[0235] c) Toluene-4-sulfonic Acid 5-acetyl-1H-pyrazol-3-yl Ester

[0236] To toluene-4-sulfonic acid 5-[(S)-l-hydroxyethyl]-1H-pyrazol-3-ylester (6.09 g, 21.6 mmol) in anhydrous dichloromethane (180 ml) wasadded pyridinium dichromate (9.74 g, 25.9 mmol) and the resulting slurrywas stirred at room temperature for 17.5 h. The mixture was poureddirectly onto a column of silica gel, which was eluted with ethylacetate to yield 5.13 g (85%) of the title compound as a whitish solid:¹H NMR (360 MHz, DMSO-d₆) δ 2.43 (3H, s), 2.45 (3H, s), 6.78 (1H, s),7.49 (2H, d, J=8.2 Hz), 7.80 (2H, d, J=8.3 Hz), 13.72 (1H, s); MS (ES⁺)m/e 281 [M+H]⁺.

[0237] d) Toluene-4-sulfonic Acid7-(2-fluorophenyl)-4-methyl-pyrazolo[1,5-d][1,2,4]triazin-2-yl Ester

[0238] A mixture of toluene-4-sulfonic acid 5-acetyl-1H-pyrazol-3-ylester (2.52 g, 8.99 mmol) and 2-fluorobenzhydrazide (1.53 g, 9.90 mmol)in xylene (110 ml) was heated at reflux for 17 h under nitrogen. Thesolvent was removed in vacuo, and the residue was heated in Dowtherm Aat 180° C. for 18 h. The mixture was poured directly onto a column ofsilica gel, which was eluted with dichloromethane, then 25%EtOAc/CH₂Cl₂, to give 3.40 g (95%) of the title compound as a brownsolid: ¹H NMR (360 MHz, CDCl₃) δ 2.45 (31H, s), 2.83 (31H, s), 6.71 (1H,s), 7.18 (1H, t, J=9.5 Hz), 7.30 (21H, d, J=7.8 Hz), 7.31 (1H, m), 7.59(1H, m), 7.66 (1H, m), 7.82 (21H, d, J=8.4 Hz); MS (ES⁺) m/e 399 [M+H]⁺.

[0239] e)7-(2-Fluorophenyl)-2-hydroxy-4-methyl-pyrazolo[1,5-d][1,2,4]triazine

[0240] To a stirred solution of toluene-4-sulfonic acid7-(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester(3.39 g, 8.51 mmol) in 1,4-dioxane (150 ml) and water (30 ml) was added4 N aqueous NaOH (10.64 ml, 42.6 mmol) and the mixture was stirred atroom temperature for 4 h. The mixture was concentrated in vacuo to about30 ml, and the aqueous residue was diluted with water (150 ml) andwashed with ethyl acetate (50 ml). The remaining aqueous layer wasacidified to pH 5 with 5 N aqueous HCl (4 ml) and the resultingprecipitate was collected by filtration, washed with water and dried at60° C. under vacuum to leave 1.98 g (95%) of the title compound as acream solid: ¹H NMR (360 MHz, DMSO-d₆) δ 2.68 (3H, s), 6.38 (1H, s),7.41-7.47 (2H, m), 7.66-7.77 (2H, m); MS (ES⁺) m/e 245 [M+H]⁺.

[0241] f)3-Bromo-7-(2-fluorophenyl)-2-hydroxy-4-methylpyrazolo[1,5-d][1,2,4]triazine

[0242] To a stirred solution of7-(2-fluorophenyl)-2-hydroxy-4-methylpyrazolo[1,5-d][1,2,4]triazine(1.48 g, 6.06 mmol) in glacial acetic acid (20 ml) was added, dropwise,bromine (0.343 ml, 6.66 mmol) and the mixture was stirred at roomtemperature for 20 min. The mixture was then diluted with water (80 ml)and the resulting solid was collected by filtration, washed with waterand dried at 60° C. under vacuum to afford 1.85 g (94%) of the titlecompound as a cream solid: ¹H NMR (360 MHz, DMSO-d₆) δ 2.88 (3H, s),7.42-7.47 (2H, m), 7.67-7.76 (2H, m); MS (ES⁺) m/e 323/325 [M+H]⁺.

[0243] g)3-Bromo-7-(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine

[0244] To a stirred solution of3-bromo-7-(2-fluorophenyl)-2-hydroxy-4-methylpyrazolo[1,5-d][1,2,4]triazine(0.5636 g, 1.74 mmol) in anhydrous DMF (28 ml) was added cesiumcarbonate (2.1927 g, 6.73 mmol) and5-chloromethyl-l-methyl-1H-[1,2,4]triazole hydrochloride (EP-A-421210)(0.3518 g, 2.09 mmol) and the mixture was stirred at room temperatureunder nitrogen for 3 days. The mixture was then filtered and the solidwashed well with ethyl acetate. The filtrates were diluted to 150 mlwith ethyl acetate and washed with saturated aqueous NH₄Cl (75 ml). Theaqueous layer was further extracted with ethyl acetate (100 ml), and thecombined extracts were dried (NaSO₄) and evaporated in vacuo. Theresidue was purified by flash chromatography (silica gel, 2%MeOH/CH₂Cl₂) to give 0.5367 g (74%) of the title compound as a yellowsolid: ¹H NMR (360 MHz, CDCl₃) δ 3.01 (3H, s), 3.85 (3H, s), 5.49 (2H,s), 7.26 (1H, m), 7.37 (1H, td, J=7.6, 0.9 Hz), 7.62 (1H, m), 7.71 (1H,m), 7.86 (1H, s); MS (ES⁺) m/e 418/420 [M+H]⁺.

[0245] h)7-(2-Fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-3-(thien-3-yl)pyrazolo[1,5-d][1,2,4]triazine

[0246] A mixture of3-bromo-7-(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine(100.7 mg, 0.241 mmol), thiophene-3-boronic acid (46.8 mg, 0.366 mmol)and cesium carbonate (157.0 mg, 0.482 mmol) in anhydrous 1,4-dioxane (10ml) was degassed by three freeze-pump-thaw cycles. Thentris(dibenzylideneacetone)dipalladium(0) (22.5 mg, 0.0246 mmol) and a0.1M solution of tri-tert-butylphosphine in 1,4-dioxane (0.58 ml, 0.058mmol) was added and two more freeze-pump-thaw cycles were performed. Themixture was heated at 90° C. under nitrogen for 22 h, then filteredthrough glass fibre paper. The solid was washed with ethyl acetate, andthe filtrates were washed with saturated aqueous NaCl (15 ml). Theaqueous layer was further extracted with ethyl acetate (25 ml), and thecombined extracts were dried (NaSO₄) and evaporated in, vacuo. Theresidue was purified by flash chromatography (silica gel, 2%MeOH/CH₂Cl₂) to give 83.8 mg (83%) of the title compound as an orangesolid: mp=124-129° C. (CH₂Cl₂-EtOAc-isohexane); ¹H NMR (360 MHz, CDCl₃)δ 2.60 (3H, s), 3.71 (3H, s), 5.46 (2H, s), 7.18 (1H, d, J=4.9 Hz), 7.27(1H, m), 7.38 (1H, m), 7.38 (1H, s), 7.44 (1H, dd, J=4.9, 3.0 Hz), 7.63(1H, m), 7.75 (1H, t, J=7.1 Hz), 7.83 (1H, s); MS (ES⁺) m/e 422 [M+H]⁺.Anal. Found C, 56.94; H, 4.04; N, 22.49%. C₂₀H₁₆FN₇OS.0.08 C₄H₈O₂requires C, 56.96; H, 3.91; N, 22.88%.

EXAMPLE 157-(2-Fluorophenyl-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-3-phenyl-pyrazolo[1,5-d][1,2,4]triazine

[0247] This was prepared in 70% yield using a similar procedure to thatdescribed in Example 14, step h, but using phenylboronic acid instead ofthiophene-3-boronic acid: mp=159-162° C. (EtOAc-isohexane); ¹H NMR (360MHz, CDCl₃) δ 2.52 (3H, s), 3.69 (3H, s), 5.46 (2H, s), 7.28 (1H, m),7.36-7.48 (6H, m), 7.63 (1H, m), 7.77 (1H, m), 7.82 (1H, s); MS (ES⁺)m/e 416 [M+H]⁺. Anal. Found C, 63.32; H, 4.36; N, 23.06%.C₂₂H₁₈FN₇O.0.06 C₄H₈O₂ requires C, 63.49; H, 4.43; N, 23.31%.

EXAMPLE 167-(2-Fluorophenyl)-3-(far-3-yl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine

[0248] This was prepared in 76% yield using a similar procedure to thatdescribed in Example 14, step h, but using furan-3-boronic acid insteadof thiophene-3-boronic acid: mp=150-153° C. (CH₂Cl₂-EtOAc-isohexane); ¹HNMR (400 MHz, CDCl₃) δ 2.70 (3H, s), 3.73 (3H, s), 5.47 (2H, s), 6.56(1H, dd J=1.9, 0.8 Hz), 7.27 (1H, m), 7.37 (1H, td, J=7.6, 1.0 Hz), 7.55(1H, t, J=1.8 Hz), 7.59-7.63 (2H, m), 7.74 (1H, m), 7.84 (1H, s); MS(ES⁺) m/e 406 [M+H]⁺. Anal. Found C, 58.33; H, 3.95; N, 23.31%.C₂₀H₁₆FN₇O₂.0.07 C₄H₈O₂.0.03 CH₂Cl₂.0.2H₂O requires C, 58.40; H, 4.11;N, 23.47%.

EXAMPLE 177-(2-Fluorophenyl)-4-methyl-2-(1-methyl-1H-[1,2,4]triazol-3-ylmethoxy)-3-(thien-3-yl)pyrazolo[1,5-d][1,2,4]triazine

[0249] a)3-Bromo-7-(2-fluorophenyl)-4-methyl-2-(1-methyl-1H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine

[0250] This was prepared in 77% yield using a similar procedure to thatdescribed in Example 14, step g, but using3-chloromethyl-1-methyl-1H-[1,2,4]triazole hydrochloride (EP-A-421210)instead of 5-chloromethyl-1-methyl-1H-[1,2,4]triazole hydrochloride andstirring for 7 days instead of 3 days: ¹H NMR (360 MHz, CDCl₃) δ 3.00(3H, s), 3.93 (3H, s), 5.42 (2H, s), 7.23 (1H, m), 7.33 (1H, td, J=7.5,0.6 Hz), 7.59 (1H, m), 7.75 (1H, m), 8.03 (1H, s); MS (ES⁺) m/e 418/420[M+H]⁺.

[0251] b)7-(2-Fluorophenyl)-4-methyl-2-(l-methyl-1H-[1,2,4]triazol-3-ylmethoxy)-3-(thien-3-yl)pyrazolo[1,5-d][1,2,4]triazine

[0252] This was prepared in 64% yield using a similar procedure to thatdescribed in Example 14, step h, but using3-bromo-7-(2-fluorophenyl)-4-methyl-2-(1-methyl-1H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazineinstead of3-bromo-7-(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine:mp=214-217° C. (CH₂Cl₂-EtOAc-isohexane); ¹H NMR (400 MHz, CDCl₃) δ 2.61(3H, s), 3.89 (3H, s), 5.41 (2H, s), 7.21-7.24 (2H, m), 7.34 (1H, td,J=7.6, 0.8 Hz), 7.37-7.42 (2H, m), 7.59 (1H, m), 7.79 (1H, m), 7.98 (1H,s); MS (ES⁺) m/e 422 [M+H]⁺. Anal. Found C, 57.00; H, 3.86; N, 23.22%.C₂₀H₁₆FN₇OS requires C, 57.00; H, 3.83; N, 23.26%.

EXAMPLE 187-(2-Fluorophenyl)-4-methyl-2-(l-methyl-1H-[1,2,3]triazol-4-ylmethoxy)-3-(thien-3-yl)pyrazolo[1,5-d][1,2,4]triazine

[0253] a) 4-Chloromethyl-1-methyl-1H-[1,2,3]triazole Hydrochloride

[0254] To thionyl chloride (20 ml) under nitrogen, cooled by an icebath, was added (1-methyl-1H-[1,2,3]triazol-4-yl)methanol hydrochloridemonohydrate (1.996 g, 11.9 mmol). The mixture was stirred for 5 minbefore removing the cooling bath and heating at reflux for 30 min. Theexcess thionyl chloride was evaporated in vacuo and the residue wastriturated with diethyl ether. The resulting solid was collected byfiltration, washed with diethyl ether and dried under vacuum at 60° C.to give the title compound as a white solid: ¹H NMR (360 MHz, DMSO-d₆) δ4.04 (3H, s), 4.81 (2H, s), 8.13 (1H, s).

[0255] b)3-Bromo-7-(2-fluorophenyl)-4-methyl-2-(1-methyl-1H-[1,2,3]triazol-4-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine

[0256] This was prepared in 75% yield using a similar procedure to thatdescribed in Example 14, step g, but using4-chloromethyl-1-methyl-1H-[1,2,3]triazole hydrochloride instead of5-chloromethyl-1-methyl-1H-[1,2,4]triazole hydrochloride and stirringfor 7 days instead of 3 days: 1H NMR (360 MHz, CDCl₃) δ 3.00 (3H, s),4.07 (3H, s), 5.48 (2H, s), 7.27 (1H, m), 7.38 (1H, t, J=7.5 Hz), 7.54(1H, s), 7.63 (1H, m), 7.75 (1H, m); MS (ES⁺) m/e 418/420 [M+H]⁺.

[0257] c)7-(2-Fluorophenyl)-4-methyl-2-(1-methyl-1H-[1,2,3]triazol-4-ylmethoxy)-3-(thien-3-yl)pyrazolo[1,5-d][1,2,4]triazine

[0258] This was prepared in 83% yield using a similar procedure to thatdescribed in Example 14, step h, but using3-bromo-7-(2-fluorophenyl)-4-methyl-2-(1-methyl-1H-[1,2,3]triazol-4-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazineinstead of3-bromo-7-(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine:mp=181-186° C. (EtOAc-isohexane); ¹H NMR (360 MHz, CDCl₃) δ 2.61 (3H,s), 4.04 (3H, s), 5.45 (2H, s), 7.17 (1H, dd, J=4.9, 1.1 Hz), 7.30 (1H,m), 7.35-7.42 (3H, m), 7.47 (1H, s), 7.64 (1H, m), 7.79 (1H, s); MS(ES⁺) m/e 422 [M+H]⁺. Anal. Found C, 56.69; H, 3.81; N, 21.33%.C₂₀H₁₆FN₇OS.0.35 C₄H₈O₂ requires C, 56.83; H, 4.19; N, 21.68%.

EXAMPLE 197-(4-Fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-3-(thien-3-yl)pyrazolo[1,5-d][1,2,4]triazine

[0259] a) Toluene-4-sulfonic Acid7-(4-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl Ester

[0260] This was prepared in 97% yield using a similar procedure to thatdescribed in Example 14, step d, but using 4-fluorobenzhydrazide insteadof 2-fluorobenzhydrazide: ¹H NMR (360 MHz, CDCl₃) δ 2.48 (3H, s), 2.81(3H, s), 6.68 (1H, s), 7.16 (2H, t, J=8.4 Hz), 7.37 (2H, d, J=8.0 Hz),7.89 (2H, d, J=8.1 Hz), 8.32 (21H, m); MS (ES⁺) m/e 399 [M+H]⁺.

[0261] b)7-(4-Fluorophenyl)-2-hydroxy-4-methylpyrazolo[1,5-d][1,2,4]triazine

[0262] This was prepared in 98% yield using a similar procedure to thatdescribed in Example 14, step e, but using toluene-4-sulfonic acid7-(4-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl esterinstead of toluene-4-sulfonic acid7-(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester: ¹HNMR (360 MHz, DMSO-d₆) δ 2.65 (3H, s), 6.33 (1H, s), 7.43 (2H, t, J=8.9Hz), 8.39 (2H, dd, J=8.9, 5.6 Hz); MS (ES⁺) m/e 245 [M+H]₊.

[0263] c)3-Bromo-7-(4-fluorophenyl)-2-hydroxy-4-methylpyrazolo[1,5-d][1,2,4]triazine

[0264] This was prepared in 98% yield using a similar procedure to thatdescribed in Example 14, step f, but using7-(4-fluorophenyl)-2-hydroxy-4-methylpyrazolo[1,5-d][1,2,4]triazineinstead of7-(2-fluorophenyl)-2-hydroxy-4-methylpyrazolo[1,5-d][1,2,4]triazine: ¹HNMR (400 MHz, DMSO-d₆) δ 2.87 (3H, s), 7.45 (2H, t, J=8.9 Hz), 8.26 (2H,dd, J=8.9 and 5.6 Hz); MS (ES⁺) m/e 323/325 [M+H]⁺.

[0265] d)3-Bromo-7-(4-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine

[0266] This was prepared in 69% yield using a similar procedure to thatdescribed in Example 14, step g, but using3-bromo-7-(4-fluorophenyl)-2-hydroxy-4-methylpyrazolo[1,5-d][1,2,4]triazineinstead of3-bromo-7-(2-fluorophenyl)-2-hydroxy-4-methylpyrazolo[1,5-d][1,2,4]triazineand stirring for 1 day instead of 3 days: ¹H NMR (360 MHz, CDCl₃) δ 3.00(3H, s), 4.00 (3H, s), 5.62 (2H, s), 7.26 (2H, t, J=8.7 Hz), 7.91 (1H,s), 8.38 (2H, dd, J=9.0, 5.4 Hz); MS (ES⁺) m/e 418/420 [M+H]⁺.

[0267] e)7-(4-Fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-3-(thien-3-yl)pyrazolo[1,5-d][1,2,4]triazine

[0268] This was prepared in 76% yield using a similar procedure to thatdescribed in Example 14, step h, but using3-bromo-7-(4-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazineinstead of3-bromo-7-(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine:mp=171-177° C. (CH₂Cl₂-EtOAc-isohexane); ¹H NMR (400 MHz, CDCl₃) δ 2.56(3H, s), 3.84 (3H, s), 5.59 (2H, s), 7.16 (1H, dd, J=-5.0, 1.2 Hz), 7.27(2H, t, J=8.8 Hz), 7.36 (1H, dd, J=3.0, 1.2 Hz), 7.45 (1H, dd, J=5.0,3.0 Hz), 7.88 (1H, s), 7.75 (2H, dd, J=9.0, 5.4 Hz); MS (ES⁺) m/e 422[M+H]⁺. Anal. Found C, 56.30; H, 3.52; N, 22.83%. C₂₀H₁₆FN₇OS.0.3H₂Orequires C, 56.28; H, 3.92; N, 22.97%.

EXAMPLE 207-(2,4-Difluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-3-(thien-3-yl)pyrazolo[1,5-d][1,2,4]triazine

[0269] a) Toluene-4-sulfonic Acid7-(2,4-difluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl Ester

[0270] This was prepared in 87% yield using a similar procedure to thatdescribed in Example 14, step d, but using 2,4-difluorobenzhydrazideinstead of 2-fluorobenzhydrazide: ¹H NMR (360 MHz, CDCl₃) δ 2.46 (3H,s), 2.83 (3H, s), 6.71 (1H, s), 6.93 (1H, td, J=7.4, 2.7 Hz), 7.05 (1H,m), 7.31 (2H, d, J=8.1 Hz), 7.68 (1H, m), 7.82 (2H, d, J=8.3 Hz); MS(ES⁺) m/e 417 [M+H]⁺.

[0271] b) 7-(2,4-Difluorophenyl-2-hydroxy-4-methyl3pyrazolo[1,5-d][1,2,4]triazine

[0272] This was prepared in 92% yield using a similar procedure to thatdescribed in Example 14, step e, but using toluene-4-sulfonic acid7-(2,4-difluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl esterinstead of toluene-4-sulfonic acid7-(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester: ¹HNMR (400 MHz, DMSO-d₆) δ 2.50 (3H, s), 6.36 (1H, s), 7.30 (1H, m), 7.52(1H, m), 7.84 (1H, td, J-=8.36, 6.52 Hz); MS (ES⁺) m/e 263 [M+H]⁺.

[0273] c)3-Bromo-7-(2,4-difluorophenyl)-2-hydroxy-4-methylpyrazolo[1,5-d][1,2,4]triazine

[0274] This was prepared in 93% yield using a similar procedure to thatdescribed in Example 14, step f, but using7-(2,4-difluorophenyl)-2-hydroxy-4-methylpyrazolo[1,5-d][1,2,4]triazineinstead of7-(2-fluorophenyl)-2-hydroxy-4-methylpyrazolo[1,5-d][1,2,4]triazine: ¹HNMR (360 MHz, DMSO-d₆) δ 2.88 (3H, s), 7.34 (1H, td, J=8.6, 2.3 Hz),7.54 (1H, td, J=9.3, 2.4 Hz), 7.83 (1H, td, J=8.31, 6.4 Hz); MS (ES⁺)m/e 340/342 [M+H]⁺.

[0275] d) 3-Bromo-7-(2,4-difluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-pyrazolo[1,5-d][1,2,4]triazine

[0276] This was prepared in 72% yield using a similar procedure to thatdescribed in Example 14, step g, but using3-bromo-7-(2,4-difluorophenyl)-2-hydroxy-4-methylpyrazolo[1,5-d][1,2,4]triazine instead of3-bromo-7-(2-fluorophenyl)-2-hydroxy-4-methylpyrazolo[1,5-d][1,2,4]triazineand stirring for 21 h instead of 3 days: ¹H NMR (360 MHz, CDCl₃) δ 3.01(3H, s), 3.93 (3H, s), 5.50 (2H, s), 7.01 (1H, m), 7.10 (1H, m), 7.72(1H, m), 7.87 (1H, s); MS (ES⁺) m/e 436/438 [M+H]⁺.

[0277] e)7-(2,4-Difluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-3-(thien-3-yl)-pyrazolo[1,5-d][1,2,4]triazine

[0278] This was prepared in 36% yield using a similar procedure to thatdescribed in Example 14, step h, but using3-bromo-7-(2,4-difluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazineinstead of3-bromo-7-(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine:mp=144-146° C. (CH₂Cl₂-EtOAc-isohexane); ¹H NMR (400 MHz, CDCl₃) δ 2.59(3H, s), 3.76 (3H, s), 5.48 (2H, s), 7.01 (1H, t, J=1.2 Hz), 7.11 (1H,d, J=2.4 Hz), 7.16 (1H, dd, J=5.0, 1.2 Hz), 7.37 (1H, dd, J=3.0, 1.2Hz), 7.44 (1H, dd, J=5.0, 3.0 Hz), 7.76 (2H, m), 7.83 (1H, s); MS (ES⁺)m/e 440 [M+H]⁺.

1. A compound of formula I, or a salt or prodrug thereof:

wherein Y represents C₁₋₆ alkyl; Z represents halogen; or C₁₋₆ alkyl,C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₆₋₈ bicycloalkyl, aryl, C₃₋₇heterocycloalkyl, heteroaryl or di(C₁₋₆)alkylamino, any of which groupsmay be optionally substituted; R¹ represents C₃₋₇ cycloalkyl, phenyl,furyl, thienyl, pyridinyl or pyrazinyl, any of which groups may beoptionally substituted; and R² represents C₃₋₇ cycloalkyl(C₁₋₆)alkyl,aryl(C₁₋₆)alkyl or heteroaryl(C₁₋₆)alkyl, any of which groups may beoptionally substituted.
 2. A compound as claimed in claim 1 representedby formula IIA, and salts and prodrugs thereof:

wherein Y, Z and R¹ are as defined in claim 1; m is 1 or 2; and R¹²represents aryl or heteroaryl, either of which groups may be optionallysubstituted.
 3. A compound as claimed in claim 2 represented by formulaIIB, and pharmaceutically acceptable salts thereof:

wherein Y and R¹ are as defined in claim 1; Q represents the residue ofa cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridinyl,furyl or thienyl ring; R^(3a) represents hydrogen, methyl, fluoro,chloro, trifluoromethyl, cyano or amino; R^(3b) represents hydrogen orfluoro; and R⁴ represents hydrogen, methyl, ethyl, n-propyl, isopropyl,fluoroethyl or difluoroethyl.
 4. A compound selected from:3,7-bis(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine;3-(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-phenylpyrazolo[1,5-d][1,2,4]triazine;3-cyclopentyl-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazine;3-cyclopentyl-7-(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine;3-cyclopentyl-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-4-methyl-7-phenyl-pyrazolo[1,5-d][1,2,4]triazine;3-cyclopentyl-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-phenylpyrazolo[1,5-d][1,2,4]triazine;and salts and prodrugs thereof.
 5. A compound selected from:3-tert-butyl-7-(2,5-difluorophenyl)-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-4-methylpyrazolo[1,5-d][1,2,4]triazine;3-tert-butyl-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-(2,3,6-trifluorophenyl)pyrazolo[1,5-d][1,2,4]triazine;3-(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-(pyrazin-2-yl)pyrazolo[1,5-d][1,2,4]triazine;3,7-bis(2-fluorophenyl)-4-methyl-2-(1-methyl-1H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine;2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-3-(2-fluorophenyl)-4-methyl-7-(thien-3-yl)pyrazolo[1,5-d][1,2,4]triazine;3-(2-fluorophenyl)-4-methyl-2-(1-methyl-1H-[1,2,4]triazol-3-ylmethoxy)-7-(thien-3-yl)pyrazolo[1,5-d][1,2,4]triazine;3-cyclohexyl-7-(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1, 2,4]triazine;7-(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-3-(thien-3-yl)pyrazolo[1,5-d][1,2,4]triazine;7-(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-3-phenylpyrazolo[1,5-d][1,2,4]triazine;7-(2-fluorophenyl)-3-(fur-3-yl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine;7-(2-fluorophenyl)-4-methyl-2-(l-methyl-1H-[1,2,4]triazol-3-ylmethoxy)-3-(thien-3-yl)pyrazolo[1,5-d][1,2,4]triazine;7-(2-fluorophenyl)-4-methyl-2-(1-methyl-1H-[1,2,3]triazol-4-ylmethoxy)-3-(thien-3-yl)pyrazolo[1,5-d][1,2,4]triazine;7-(4-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-3-(thien-3-yl)pyrazolo[1,5-d][1,2,4]triazine;7-(2,4-difluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-3-(thien-3-yl)pyrazolo[1,5-d][1,2,4]triazine;and salts and prodrugs thereof.
 6. A pharmaceutical compositioncomprising a compound of formula I as defined in claim 1 or apharmaceutically acceptable salt thereof or a prodrug thereof inassociation with a pharmaceutically acceptable carrier.
 7. The use of acompound of formula I as defined in claim 1 or a pharmaceuticallyacceptable salt thereof or a prodrug thereof for the manufacture of amedicament for the treatment and/or prevention of anxiety.
 8. A processfor the preparation of a compound as claimed in claim 1, whichcomprises: (A) cyclising a compound of formula III:

wherein Y, Z, R¹ and R² are as defined in claim 1; or (B) reacting acompound of formula VI with a compound of formula

wherein Y, Z, R¹ and R² are as defined in claim 1, and L¹ represents asuitable leaving group; or (C) reacting a compound of formula IX with acompound of formula X:

wherein Y, Z, R¹ and R² are as defined in claim 1, and 1, represents asuitable leaving group; or (D) reacting a compound of formula XII with acompound of formula XIII:

wherein Y, Z, R¹ and R² are as defined in claim 1, L³ represents asuitable leaving group, and M represents —B(OH)₂ or a cyclic esterthereof formed with an organic diol, or M represents —Sn(Alk)₃ in whichAlk represents a C₁₋₆ alkyl group; in the presence of a transition metalcatalyst; and (E) subsequently, if desired, converting a compound offormula I initially obtained into a further compound of formula I bystandard methods.
 9. A method for the treatment and/or prevention ofanxiety which comprises administering to a patient in need of suchtreatment an effective amount of a compound of formula I as defined inclaim 1 or a pharmaceutically acceptable salt thereof or a prodrugthereof.